A total of 2188 articles were identified using database searching, and 2085 were recorded after duplicates removal. 1775 were excluded after screening of title/abstract, 175 were finally excluded, and 5 articles were excluded during data extraction. Finally, 130 articles were included as references.
Pro-inflammatory Cytokines in PD Development:
1. TNF-α in Parkinson's Pathogenesis:
Dysregulations leading to switching of neurons towards Lewy Body Buildup:
Tumor necrosis factor-alpha (TNF-α) is a cytokine recognized for its pivotal role in inflammation and immune responses, with emerging implications in neurodegenerative diseases like Parkinson's disease (PD) [17]. Within the context of PD, TNF-α has been implicated in disease progression through various mechanisms, foremost among them being neuroinflammation [18]. TNF-α serves as a crucial mediator in neuroinflammation, initiating a cascade of inflammatory responses that activate microglia and astrocytes, subsequently releasing pro-inflammatory mediators. This chronic inflammation is instrumental in neuronal damage and dysfunction, contributing to the formation of Lewy bodies, a characteristic pathological feature of PD [19].
Moreover, TNF-α exerts its influence on PD pathogenesis by inducing oxidative stress, a hallmark of the disease intimately linked with the aggregation of α-synuclein into Lewy bodies [20]. Through the promotion of reactive oxygen species (ROS) generation and the impairment of antioxidant defense mechanisms in neurons, TNF-α exacerbates oxidative stress, exacerbating neuronal dysfunction [21]. Additionally, TNF-α disrupts protein clearance mechanisms such as autophagy and the ubiquitin-proteasome system (UPS), leading to the accumulation of misfolded proteins, including α-synuclein, further propagating Lewy body formation [22].
Furthermore, prolonged exposure to elevated levels of TNF-α directly impacts neuronal viability by activating cell death pathways, including apoptosis and necroptosis [23]. This culminates in the loss of dopaminergic neurons in the substantia nigra, a hallmark of PD pathology [24]. Additionally, TNF-α modulates the aggregation and accumulation of α-synuclein, potentially promoting its misfolding and aggregation, thus contributing to Lewy body formation. In light of these numerous roles of TNF-α in PD pathogenesis, targeting TNF-α signaling pathways holds promise as a therapeutic strategy for intervening in the pathological processes underlying PD and other neurodegenerative diseases [25].
Subsequent disruptions harming neuronal homeostasis and cell survival signals:
Inflammation, inclusive of TNF-α actions, can severely disrupt neuronal homeostasis and jeopardize cell survival signals through diverse mechanisms. One such mechanism involves excitotoxicity, wherein inflammatory mediators like TNF-α dysregulate glutamate signaling, culminating in excessive activation of glutamate receptors such as NMDA receptors [26]. This aberrant activation leads to an influx of calcium ions into neurons, precipitating cellular damage and eventual demise [27]. Moreover, TNF-α has been documented to augment glutamate release while inhibiting its reuptake, exacerbating excitotoxic neuronal injury [28].
Another consequential mechanism through which inflammatory cytokines like TNF-α inflict harm is by promoting oxidative stress within neurons [29]. TNF-α can incite the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) within neuronal environments. The overwhelming production of ROS/RNS overwhelms the cell's antioxidant defense mechanisms, resulting in oxidative stress [30]. Consequently, this oxidative stress can inflict damage upon critical cellular components such as lipids, proteins, and DNA, thereby fostering neuronal dysfunction and eventual demise [31].
Furthermore, TNF-α's impact extends to disrupting mitochondrial function within neurons, manifesting as impaired mitochondrial respiration, reduced ATP production, and the liberation of pro-apoptotic factors. This disruption not only compromises energy metabolism but also amplifies ROS/RNS production, thereby exacerbating oxidative stress and further compromising neuronal viability [32]. Additionally, TNF-α can activate apoptotic signaling pathways within neurons, tipping the balance towards apoptosis [33]. While TNF-α can trigger both apoptotic and pro-survival signaling depending on cellular context, sustained or excessive TNF-α signaling often leans towards apoptosis, activating caspases and prompting the release of cytochrome c from mitochondria to initiate the intrinsic apoptotic pathway [34].
Implications of TNF-α in decreasing stemness of NSCs in development of PD:
Elevated levels of TNF-α in the brain have been linked to adverse effects on the stemness of neural stem cells (NSCs), potentially impacting neurogenesis and neuronal repair processes [35]. One significant pathway through which increased TNF-α levels exert their influence is the inhibition of NSC proliferation [36]. TNF-α can induce cell cycle arrest or promote apoptosis in NSCs, leading to a reduction in the pool of stem cells available for neurogenesis and repair mechanisms. This decline in NSC proliferation may contribute to the reduction in neurogenesis characteristic of neurodegenerative disorders marked by elevated TNF-α levels [37].
Moreover, TNF-α can alter the differentiation trajectory of NSCs, favoring differentiation into glial cells over neurons. This shift towards glial lineages, such as astrocytes and microglia, may exacerbate inflammatory responses in the brain, further hindering neuronal regeneration and repair [38]. Additionally, TNF-α disrupts the migration of NSCs towards sites of injury or neurogenic niches within the brain, impeding their recruitment to areas requiring neuronal replacement or repair, and thereby impairing neurogenesis [39].
Furthermore, TNF-α's detrimental effects extend to compromising NSC survival, either through direct induction of apoptosis or sensitization to apoptotic signals. Sustained exposure to elevated TNF-α levels may compromise NSC viability, diminishing their capacity for self-renewal and differentiation [40]. Notably, TNF-α-mediated neuroinflammation and oxidative stress also contribute to the formation and accumulation of Lewy bodies, characteristic protein aggregates in Parkinson's disease (PD) [41]. The interaction between TNF-α and Lewy body formation may create a toxic microenvironment detrimental to NSC function and stemness, exacerbating neurodegeneration. Collectively, these findings underscore the intricate relationship between inflammation, NSC function, and disease pathology in neurodegenerative conditions, suggesting potential therapeutic avenues targeting TNF-α signaling pathways to preserve NSC stemness and promote neuroregeneration [42].
2. IL-1β in Parkinson's Pathogenesis:
Dysregulations leading to switching of neurons towards Lewy Body Buildup:
Interleukin-1 beta (IL-1β) is a pro-inflammatory cytokine known for its pivotal role in immune response regulation and inflammation [1]. In the context of neurodegenerative diseases like Parkinson's disease (PD), IL-1β has emerged as a significant contributor to neuroinflammation and disease progression, notably implicating the formation of Lewy bodies [10]. IL-1β's heightened expression in the brain sets the stage for a cascade of detrimental effects, potentially shifting neurons towards Lewy body accumulation [43].
One prominent effect of IL-1β is its induction of neuroinflammation, wherein it acts as a potent stimulator triggering the activation of microglia and astrocytes. These activated glial cells release an array of pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS), fostering a neuroinflammatory milieu [44]. This chronic inflammation is closely linked with neuronal damage, creating favorable conditions for the accumulation of pathological protein aggregates, particularly α-synuclein, the primary component of Lewy bodies [45].
Moreover, IL-1β directly influences α-synuclein aggregation and accumulation, a pivotal process in Lewy body formation [46]. Research indicates that IL-1β modulates the expression and phosphorylation state of α-synuclein, promoting its misfolding and aggregation into insoluble fibrils characteristic of Lewy bodies. This exacerbation of α-synuclein aggregation by IL-1β underscores its role in driving the pathological protein accumulation observed in PD [47].
Furthermore, IL-1β disrupts essential protein clearance mechanisms such as autophagy and the ubiquitin-proteasome system (UPS), responsible for degrading misfolded proteins like α-synuclein [48]. Dysfunction in these clearance pathways leads to the accumulation of toxic protein aggregates, including Lewy bodies, within neurons. Additionally, IL-1β-mediated oxidative stress further contributes to neuronal damage, facilitating α-synuclein aggregation and Lewy body formation [49]. Dysregulation of neuronal homeostasis by IL-1β alters synaptic function, neurotransmitter signaling, and neuronal excitability, exacerbating α-synuclein accumulation and Lewy body formation. Overall, targeting IL-1β signaling pathways presents a promising therapeutic approach for attenuating neuroinflammation and slowing the progression of Lewy body-associated neurodegenerative diseases like PD [50].
Subsequent disruptions harming neuronal homeostasis and cell survival signals:
Inflammation, particularly driven by IL-1β, disrupts neuronal homeostasis and undermines cell survival signals through a multitude of mechanisms. One significant pathway involves neuroinflammation-induced excitotoxicity, where IL-1β exacerbates the process by promoting glutamate release and inhibiting its reuptake [51]. This results in sustained activation of glutamate receptors, calcium influx into neurons, and subsequent activation of cell death pathways, ultimately compromising neuronal survival. Additionally, IL-1β induces oxidative stress by stimulating the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) within neurons and glial cells [52]. The overwhelming generation of ROS/RNS overwhelms cellular antioxidant defenses, leading to oxidative stress and subsequent damage to cellular components, impairing neuronal function and viability [50].
Furthermore, IL-1β disrupts mitochondrial function in neurons, impairing mitochondrial respiration, reducing ATP production, and promoting mitochondrial permeability transition. This dysfunction not only leads to energy depletion but also exacerbates neuronal injury and cell death through ROS generation and release of pro-apoptotic factors [43]. Moreover, IL-1β activates apoptotic signaling pathways within neurons, stimulating the expression of pro-apoptotic genes, activating caspases, and disrupting mitochondrial integrity, thereby triggering the intrinsic apoptotic pathway. Additionally, IL-1β may sensitize neurons to apoptotic stimuli, rendering them more susceptible to cell death [48].
Additionally, IL-1β inhibits the expression of neurotrophic factors critical for neuronal survival and function, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). This reduction in neurotrophic support compromises neuronal viability and plasticity, exacerbating neuronal damage and dysfunction [47]. Furthermore, IL-1β disrupts synaptic transmission and plasticity, impairing neuronal communication and network activity. The alterations in synaptic function contribute to neuronal instability and hyperexcitability, further exacerbating neuronal dysfunction and degeneration observed in various neurodegenerative diseases and neurological disorders [44]. Therapeutic strategies targeting inflammation modulation and restoration of neuronal homeostasis hold promise for attenuating neuronal damage and promoting neuroprotection in such conditions [49].
Implications of IL-1β in decreasing stemness of NSCs in development of PD:
Elevated levels of IL-1β in the brain pose significant challenges to the stemness of neural stem cells (NSCs), potentially compromising their capacity to contribute to neurogenesis and neuronal repair processes, particularly in neurodegenerative diseases like Parkinson's disease (PD). IL-1β's impact on NSCs involves various mechanisms, starting with the inhibition of NSC proliferation [51]. IL-1β can induce cell cycle arrest or promote apoptosis in NSCs, activating signaling pathways that suppress their proliferation. Consequently, the reduction in NSC proliferation diminishes the pool of stem cells available for neurogenesis and repair, contributing to the observed decline in neurogenesis associated with elevated IL-1β levels in neurodegenerative disorders [52].
Furthermore, IL-1β promotes the premature differentiation of NSCs into glial cells at the expense of neuronal lineages. Glial cells, such as astrocytes and microglia, play crucial roles in neuroinflammation and may exacerbate inflammatory responses in the brain [46]. The redirection of NSC differentiation towards glial lineages diminishes the availability of neuronal precursors, impairing neuronal regeneration and repair mechanisms essential for combating neurodegenerative conditions [53].
Moreover, IL-1β disrupts the migration of NSCs towards injury sites or neurogenic niches within the brain, which is vital for their recruitment to areas requiring neuronal replacement or repair. Elevated IL-1β levels perturb chemotactic signaling pathways or alter the extracellular matrix composition, hindering NSC migration and impairing their ability to contribute to neurogenesis [54]. Additionally, IL-1β's adverse effects extend to compromising NSC survival by inducing apoptosis or sensitizing them to apoptotic signals, thereby diminishing their capacity for self-renewal and differentiation. This impairment of NSC viability exacerbates the decline in neurogenesis observed in neurodegenerative conditions like PD. Furthermore, IL-1β-mediated neuroinflammation and oxidative stress promote the formation and accumulation of Lewy bodies, protein aggregates characteristic of PD, which further disrupt NSC function and stemness [45]. Consequently, targeting IL-1β signaling pathways emerges as a promising therapeutic strategy for preserving NSC stemness and promoting neuroregeneration in neurodegenerative diseases [55].
3. IL-6 in Parkinson's Pathogenesis:
Dysregulations leading to switching of neurons towards Lewy Body Buildup:
Interleukin-6 (IL-6) stands out as a multifunctional cytokine pivotal in regulating immune responses, inflammation, and various physiological processes. However, in the context of neurodegenerative diseases such as Parkinson's disease (PD), heightened expression of IL-6 in the brain correlates with neuroinflammation and disease progression, including the formation of Lewy bodies. IL-6's influence on neurons, particularly regarding Lewy body buildup, unfolds through several interconnected mechanisms [56].
IL-6 plays a central role in inducing neuroinflammation by stimulating the activation of microglia and astrocytes in the brain. This activation triggers the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS), culminating in a neuroinflammatory environment conducive to neuronal damage and dysfunction [57]. Consequently, the chronic neuroinflammation promoted by IL-6 creates a favorable milieu for the accumulation of pathological protein aggregates, notably α-synuclein, the primary constituent of Lewy bodies [58].
Moreover, IL-6 exerts a direct influence on α-synuclein expression and aggregation, further exacerbating Lewy body pathology. It may enhance α-synuclein expression in neurons, fostering its misfolding and aggregation into insoluble fibrils characteristic of Lewy bodies [59]. Additionally, IL-6 can exacerbate α-synuclein aggregation by inducing oxidative stress and impeding protein clearance mechanisms, thereby amplifying Lewy body accumulation within neurons [60].
Furthermore, IL-6 disrupts essential protein clearance mechanisms, including autophagy and the ubiquitin-proteasome system (UPS), responsible for degrading misfolded proteins like α-synuclein. Dysfunction in these clearance pathways results in the buildup of toxic protein aggregates, including Lewy bodies, within neurons. Additionally, IL-6-mediated oxidative stress further compounds neuronal damage, facilitating α-synuclein aggregation and Lewy body formation [61]. The dysregulation of neurotrophic support by IL-6, altering the expression and signaling of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), further compromises neuronal viability and plasticity, exacerbating neuronal dysfunction and vulnerability to pathological insults. Collectively, targeting IL-6 signaling pathways emerges as a potential therapeutic avenue for attenuating neuroinflammation and mitigating Lewy body pathology in neurodegenerative diseases like PD [62].
Subsequent disruptions harming neuronal homeostasis and cell survival signals:
Inflammation, including the influence of IL-6, significantly disrupts neuronal homeostasis and undermines cell survival signals through various interconnected mechanisms [63]. One notable pathway involves the exacerbation of excitotoxicity by IL-6, wherein excessive glutamate release induces neuronal damage and death. IL-6 facilitates glutamate release while inhibiting reuptake, sustaining glutamate receptor activation and subsequent calcium influx into neurons. This disturbance in intracellular calcium homeostasis activates proteases and initiates cell death pathways, ultimately compromising neuronal survival [64].
Furthermore, IL-6 triggers the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) within neurons and glial cells, leading to oxidative stress. The overwhelming generation of ROS/RNS surpasses cellular antioxidant defenses, causing damage to lipids, proteins, and DNA, thereby impairing neuronal function and viability [56]. Additionally, IL-6 disrupts mitochondrial function in neurons, impairing respiration, reducing ATP production, and promoting mitochondrial permeability transition [65]. Consequently, mitochondrial dysfunction exacerbates neuronal injury and cell death through energy depletion, ROS generation, and release of pro-apoptotic factors [57].
Moreover, IL-6 activates apoptotic signaling pathways within neurons, stimulating the expression of pro-apoptotic genes, activating caspases, and disrupting mitochondrial integrity [58]. This activation of the intrinsic apoptotic pathway, coupled with IL-6's potential to sensitize neurons to apoptotic stimuli, renders them more susceptible to cell death. Additionally, IL-6 suppresses the expression of neurotrophic factors critical for neuronal survival and function, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), thereby compromising neuronal viability and plasticity [66].
Eventually, IL-6 disrupts synaptic transmission and plasticity, impairing neuronal communication and network activity. By altering the balance between excitatory and inhibitory neurotransmission, IL-6 induces synaptic dysfunction and neuronal hyperexcitability, ultimately contributing to neuronal instability and susceptibility to injury [59]. Overall, these various pathological processes orchestrated by inflammation, including IL-6, collectively contribute to neuronal dysfunction and degeneration observed in various neurodegenerative diseases and neurological disorders. Therapeutic interventions targeting inflammation modulation and restoration of neuronal homeostasis hold promise for attenuating neuronal damage and promoting neuroprotection in such conditions [67].
Implications of IL-6 in decreasing stemness of NSCs in development of PD:
Elevated IL-6 levels in the brain have detrimental effects on the stemness of neural stem cells (NSCs), potentially compromising neurogenesis and neuronal repair. This impact is varied, involving interactions with Lewy body emergence in neurodegenerative diseases such as Parkinson's disease (PD) [60].
One mechanism through which IL-6 diminishes NSC stemness is by inhibiting their proliferation. IL-6 activates signaling pathways that induce cell cycle arrest or apoptosis in NSCs, disrupting the balance between proliferation and differentiation [61]. Consequently, the pool of stem cells available for neurogenesis decreases, contributing to the observed decline in neurogenic capacity in neurodegenerative disorders characterized by increased IL-6 expression [62].
Moreover, IL-6 promotes the differentiation of NSCs into glial cells rather than neuronal lineages. This skewed differentiation reduces the availability of neuronal precursors, impairing neuronal regeneration and repair mechanisms. Glial cells, such as astrocytes and microglia, contribute to neuroinflammatory processes, exacerbating inflammation in the brain and further hindering neurogenesis [63].
Additionally, IL-6 disrupts the migration of NSCs towards neurogenic niches or sites of injury within the brain. NSC migration is essential for their recruitment to areas requiring neuronal replacement or repair [64]. Elevated IL-6 levels may interfere with chemotactic signaling pathways or alter the extracellular matrix composition, hindering NSC migration and impairing their ability to contribute to neurogenesis [65].
Furthermore, IL-6 can directly induce apoptosis in NSCs or sensitize them to apoptotic signals, resulting in decreased NSC survival. This susceptibility to inflammatory insults, particularly sustained exposure to elevated IL-6 levels, compromises NSC viability, further diminishing their capacity for self-renewal and differentiation [66]. Moreover, IL-6-mediated neuroinflammation and oxidative stress enhance the formation and accumulation of Lewy bodies, protein aggregates characteristic of PD. These effects collectively contribute to the dysregulation of neurogenesis and neuronal repair processes observed in PD and other neurodegenerative diseases. Targeting IL-6 signaling pathways may offer a promising therapeutic strategy for preserving NSC stemness and promoting neuroregeneration in such conditions [67, 68].
4. IL-12 in Parkinson's Pathogenesis:
Dysregulations leading to switching of neurons towards Lewy Body Buildup:
Interleukin-12 (IL-12) is a heterodimeric cytokine primarily recognized for its involvement in regulating immune responses, particularly by promoting the differentiation of T-helper 1 (Th1) cells and enhancing cell-mediated immunity [76, 78]. However, its role in the central nervous system (CNS) and neurodegenerative diseases such as Parkinson's disease (PD) remains less understood. Nevertheless, emerging evidence suggests that dysregulation of IL-12 expression in the brain could potentially contribute to neuroinflammation and the pathogenesis of PD, including the formation of Lewy bodies [69].
IL-12 can induce neuroinflammation by activating microglia and astrocytes in the brain, which subsequently release pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS) [75]. This inflammatory environment chronically contributes to neuronal damage and dysfunction, facilitating the accumulation of pathological protein aggregates like α-synuclein, the principal component of Lewy bodies [70].
Moreover, IL-12 may modulate the expression and aggregation of α-synuclein, intensifying Lewy body pathology in PD [74]. The neuroinflammation and oxidative stress induced by IL-12 may promote the misfolding and aggregation of α-synuclein, culminating in the formation of insoluble fibrils characteristic of Lewy bodies. Additionally, IL-12-mediated impairment of protein clearance mechanisms could exacerbate α-synuclein accumulation within neurons [71].
Furthermore, IL-12 can disrupt protein clearance mechanisms, including autophagy and the ubiquitin-proteasome system (UPS), responsible for degrading misfolded proteins like α-synuclein. Dysfunctional protein clearance pathways lead to the accumulation of toxic protein aggregates, including Lewy bodies, within neurons [73]. IL-12-mediated inhibition of protein clearance mechanisms exacerbates the burden of pathological protein aggregates and neuronal dysfunction. This cascade of events underscores the potential contribution of IL-12 to Lewy body pathology and neuronal dysfunction in PD, warranting further research to elucidate its role fully and explore its therapeutic potential [72].
Subsequent disruptions harming neuronal homeostasis and cell survival signals:
Inflammation, including the actions of IL-12, can profoundly disrupt neuronal homeostasis and undermine cell survival signals through a variety of mechanisms. One such mechanism involves neuroinflammation-induced excitotoxicity, where IL-12 contributes to the excessive release of glutamate, inhibiting its reuptake and leading to sustained activation of glutamate receptors, ultimately compromising neuronal survival by disrupting calcium homeostasis and triggering cell death pathways [73].
Moreover, IL-12 stimulates the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) within neurons and glial cells, inducing oxidative stress [71]. This oxidative stress damages vital cellular components, including lipids, proteins, and DNA, impairing neuronal function and viability, thereby exacerbating neuronal injury and cell death [74].
Additionally, IL-12 disrupts mitochondrial function in neurons, impeding mitochondrial respiration, reducing ATP production, and promoting mitochondrial permeability transition [70]. This mitochondrial dysfunction further exacerbates neuronal injury and cell death, contributing to the overall disruption of neuronal homeostasis and compromising cell survival signals [75].
Furthermore, IL-12 activates apoptotic signaling pathways within neurons, stimulating the expression of pro-apoptotic genes, activating caspases, and disrupting mitochondrial integrity, ultimately leading to cell death [69]. Additionally, IL-12 suppresses the expression of neurotrophic factors critical for neuronal survival and function, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), further compromising neuronal viability and plasticity [76].
Moreover, IL-12 disrupts synaptic transmission and plasticity, impairing neuronal communication and network activity. This dysregulation of synaptic function contributes to neuronal instability and susceptibility to injury, collectively contributing to the neuronal dysfunction and degeneration observed in various neurodegenerative diseases and neurological disorders [78]. Therapeutic strategies targeting inflammation and aiming to restore neuronal homeostasis hold promise for attenuating neuronal damage and promoting neuroprotection in such conditions [77].
Implications of IL-12 in decreasing stemness of NSCs in development of PD:
Increased levels of IL-12 in the brain can potentially diminish the stemness of neural stem cells (NSCs), thereby impairing their capacity to contribute to neurogenesis and neuronal repair processes [69, 70]. Elevated IL-12 levels may decrease NSC stemness through various mechanisms, particularly concerning their interactions with Lewy body emergence in neurodegenerative diseases like Parkinson's disease (PD) [71, 79].
One mechanism by which IL-12 influences NSC stemness is through the inhibition of NSC proliferation. IL-12 can activate signaling pathways that induce cell cycle arrest or apoptosis in NSCs, disrupting the balance between proliferation and differentiation and ultimately reducing the pool of stem cells available for neurogenesis [72]. This inhibition of NSC proliferation is implicated in the decline in neurogenic capacity observed in neurodegenerative disorders characterized by increased IL-12 expression [77].
Moreover, IL-12 may promote the differentiation of NSCs into glial cells rather than neuronal lineages. Glial cells, such as astrocytes and microglia, play roles in neuroinflammatory processes and may exacerbate inflammation in the brain. The shift in NSC differentiation towards glial lineages not only reduces the availability of neuronal precursors but also impairs neuronal regeneration and repair mechanisms, further contributing to neurodegeneration [69, 1].
Additionally, IL-12 can disrupt the migration of NSCs towards neurogenic niches or sites of injury within the brain, hindering their recruitment to areas requiring neuronal replacement or repair. Furthermore, IL-12-mediated neuroinflammation and oxidative stress can enhance the formation and accumulation of Lewy bodies, characteristic protein aggregates in PD [74, 75]. This detrimental cascade of events collectively contributes to the dysregulation of neurogenesis and neuronal repair processes observed in neurodegenerative diseases. Targeting IL-12 signaling pathways may hold promise as a therapeutic strategy for preserving NSC stemness and promoting neuroregeneration in such conditions [69, 78].
5. IL-18 in Parkinson's Pathogenesis
Dysregulations leading to switching of neurons towards Lewy Body Buildup:
Interleukin-18 (IL-18) is a pro-inflammatory cytokine with significant implications for immune response regulation and inflammation [88]. In the context of neurodegenerative diseases like Parkinson's disease (PD), elevated levels of IL-18 in the brain have been linked to neuroinflammation and disease progression, including the formation of Lewy bodies. Enhanced IL-18 expression within the brain could significantly influence neuronal function and contribute to the buildup of Lewy bodies, a hallmark of PD pathology [79, 87].
IL-18's role in inducing neuroinflammation is particularly notable, as it can activate microglia and astrocytes in the brain. This activation leads to the release of pro-inflammatory mediators such as cytokines, chemokines, and reactive oxygen species (ROS), establishing a neuroinflammatory microenvironment [86]. Chronic neuroinflammation is detrimental to neurons, fostering damage and dysfunction while creating conditions conducive to the aggregation of pathological proteins like α-synuclein, a major constituent of Lewy bodies [80].
Moreover, IL-18 may directly impact α-synuclein expression and aggregation, potentially exacerbating Lewy body formation [85]. IL-18-induced neuroinflammation and oxidative stress can contribute to the misfolding and aggregation of α-synuclein, culminating in the formation of insoluble fibrils characteristic of Lewy bodies. Additionally, IL-18-mediated disruption of protein clearance mechanisms, including autophagy and the ubiquitin-proteasome system (UPS), further facilitates the accumulation of α-synuclein aggregates within neurons, exacerbating neuronal dysfunction and degeneration [81].
Furthermore, IL-18 promotes oxidative stress within neurons and glial cells, leading to the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [84]. This oxidative stress damages cellular components, compromises neuronal function, and facilitates the aggregation of α-synuclein, contributing to Lewy body formation. Additionally, IL-18 dysregulates neurotrophic support by altering the expression and signaling of neurotrophic factors, further compromising neuronal viability and plasticity [83]. Overall, increased IL-18 levels in the brain are implicated in neuroinflammation, α-synuclein aggregation, impaired protein clearance mechanisms, oxidative stress, and dysregulation of neurotrophic support, all of which contribute to Lewy body buildup and neuronal dysfunction in PD. However, comprehensive research is necessary to fully understand IL-18's role in PD pathology and its potential as a therapeutic target for mitigating Lewy body pathology [82].
Subsequent disruptions harming neuronal homeostasis and cell survival signals:
Inflammation, particularly mediated by IL-18, exerts significant disruptions on neuronal homeostasis, leading to compromised cell survival signals via multiple mechanisms [82]. One such mechanism is excitotoxicity, where IL-18's involvement contributes to excessive glutamate release, inhibiting reuptake and culminating in sustained activation of glutamate receptors. Consequently, intracellular calcium homeostasis is disturbed, initiating protease activation and cell death pathways, ultimately jeopardizing neuronal survival [83].
Moreover, IL-18 stimulates the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), inducing oxidative stress within neurons and glial cells. The resultant oxidative damage to cellular components impairs neuronal function and viability [81]. Additionally, IL-18 disrupts mitochondrial function in neurons, hampering mitochondrial respiration and ATP production while promoting mitochondrial permeability transition. This dysfunction leads to energy depletion, ROS generation, and the release of pro-apoptotic factors, exacerbating neuronal injury and cell death [84].
Furthermore, IL-18's induction of apoptotic signaling pathways within neurons contributes to cell death by stimulating the expression of pro-apoptotic genes, activating caspases, and compromising mitochondrial integrity. Additionally, IL-18 suppresses the expression of neurotrophic factors critical for neuronal survival and function, thus reducing neurotrophic support and compromising neuronal viability and plasticity. Dysregulation of synaptic function, induced by IL-18, further exacerbates neuronal instability and susceptibility to injury, disrupting neuronal communication and network activity [80]. Overall, these pathogenic mechanisms, including excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptotic signaling, neurotrophic support inhibition, and synaptic function dysregulation, contribute to neuronal dysfunction and degeneration seen in various neurodegenerative diseases and neurological disorders. Therapeutic interventions targeting inflammation modulation and neuronal homeostasis restoration hold promise for mitigating neuronal damage and promoting neuroprotection in such conditions [85].
Implications of IL-18 in decreasing stemness of NSCs in development of PD:
Elevated levels of IL-18 within the brain pose a potential threat to the stemness of neural stem cells (NSCs), thereby impeding their pivotal role in neurogenesis and neuronal repair processes. This adverse impact can be traced through various avenues, particularly in the context of neurodegenerative diseases such as Parkinson's disease (PD) [79]. One notable effect is the inhibition of NSC proliferation induced by IL-18, activating signaling pathways that either arrest the cell cycle or trigger apoptosis. Such disruption in the delicate balance between proliferation and differentiation within NSCs could significantly deplete the pool of stem cells available for neurogenesis, exacerbating the decline observed in neurodegenerative disorders associated with heightened IL-18 expression [86].
Furthermore, IL-18's influence extends to promoting the differentiation of NSCs into glial cells, diverting their trajectory away from neuronal lineages. This shift towards glial lineages, including astrocytes and microglia, holds implications for exacerbating neuroinflammatory processes in the brain [90]. Consequently, the diminished availability of neuronal precursors hampers the regenerative capacity of neurons, thereby impairing repair mechanisms vital for mitigating neurodegenerative conditions [87].
Moreover, IL-18 disrupts the migration of NSCs towards neurogenic niches or sites of injury within the brain, hindering their essential role in neuronal replacement or repair. Such interference, attributed to alterations in chemotactic signaling pathways or extracellular matrix composition, compromises the ability of NSCs to contribute effectively to neurogenesis [89]. Additionally, IL-18's capacity to induce apoptosis or sensitize NSCs to apoptotic signals further undermines their survival, exacerbating the decline in neurogenesis observed in neurodegenerative contexts. This detrimental cascade is compounded by IL-18-mediated neuroinflammation and oxidative stress, culminating in the formation and accumulation of Lewy bodies—a hallmark pathology of PD. Consequently, the interplay between IL-18 and Lewy body formation creates a toxic microenvironment detrimental to NSC function and stemness, ultimately contributing to the dysregulation of neurogenesis and neuronal repair observed in PD. Targeting IL-18 signaling pathways emerges as a promising therapeutic avenue for preserving NSC stemness and fostering neuroregeneration in the face of neurodegenerative challenges [88].
6. IL-23 in Parkinson's Pathogenesis:
Dysregulations leading to switching of neurons towards Lewy Body Buildup:
Research on interleukin-23 (IL-23), a pro-inflammatory cytokine primarily known for its role in immune regulation, has begun to shed light on its potential involvement in neurological disorders such as Parkinson's disease (PD) [100]. While not as extensively studied in the context of the brain and neurodegenerative diseases, emerging evidence suggests that dysregulation of IL-23 expression within the brain could contribute to neuroinflammation and the pathogenesis of PD, including the formation of Lewy bodies—a hallmark of the disease [91].
One significant avenue through which IL-23 exerts its influence is the induction of neuroinflammation [99]. By activating microglia and astrocytes, IL-23 prompts the release of pro-inflammatory mediators and reactive oxygen species (ROS), creating an environment conducive to neuronal damage and dysfunction. Chronic neuroinflammation not only fosters the accumulation of pathological protein aggregates like α-synuclein but also perpetuates a cycle of neuronal injury characteristic of PD [92].
Moreover, IL-23 may directly influence α-synuclein, a protein intimately associated with Lewy body pathology in PD. IL-23-induced neuroinflammation and oxidative stress could foster the misfolding and aggregation of α-synuclein, exacerbating its accumulation within neurons [98]. Additionally, IL-23's interference with protein clearance mechanisms, such as autophagy and the ubiquitin-proteasome system, further compounds the burden of pathological protein aggregates, contributing to neuronal dysfunction and degeneration [93].
Furthermore, IL-23 promotes oxidative stress within neurons and glial cells, overwhelming cellular antioxidant defenses and facilitating α-synuclein aggregation [97]. The dysregulation of neurotrophic support, characterized by altered expression and signaling of neurotrophic factors like BDNF and NGF, further compromises neuronal viability and plasticity. Collectively, these mechanisms underscore the potential significance of IL-23 in driving neuroinflammation, α-synuclein aggregation, and neuronal dysfunction in PD, warranting further investigation into its therapeutic potential as a target for mitigating Lewy body pathology [94].
Subsequent disruptions harming neuronal homeostasis and cell survival signals:
Inflammation, orchestrated by cytokines like IL-23, can severely disrupt the delicate balance of neuronal homeostasis, leading to detrimental outcomes for cell survival. One prominent mechanism through which IL-23 exerts its deleterious effects is excitotoxicity, where excessive glutamate release triggers neuronal damage and death [96]. IL-23 instigates glutamate release while impeding its reuptake, causing sustained activation of glutamate receptors and subsequent calcium influx into neurons. This disruption in intracellular calcium dynamics initiates protease activation and sets off cell death pathways, ultimately compromising neuronal viability [95].
Moreover, IL-23 instigates oxidative stress by stimulating the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) within neurons and glial cells. The overwhelming generation of ROS and RNS overwhelms cellular antioxidant defenses, resulting in oxidative damage to lipids, proteins, and DNA, thereby impairing neuronal function and viability [95]. Concurrently, IL-23 disrupts mitochondrial function in neurons, compromising mitochondrial respiration, reducing ATP production, and fostering mitochondrial permeability transition. These mitochondrial aberrations culminate in energy depletion, increased ROS production, and the release of pro-apoptotic factors, exacerbating neuronal injury and cell death [96].
Furthermore, IL-23 activates apoptotic signaling pathways within neurons, exacerbating cell death. By stimulating the expression of pro-apoptotic genes, activating caspases, and compromising mitochondrial integrity, IL-23 primes neurons for apoptotic demise [94]. Additionally, IL-23's suppression of neurotrophic factors critical for neuronal survival, such as BDNF and NGF, further undermines neuronal viability and plasticity. Dysregulated synaptic function induced by IL-23 further exacerbates neuronal instability and susceptibility to injury, as it disrupts communication and network activity among neurons. Collectively, these mechanisms underscore the profound impact of IL-23-mediated inflammation on neuronal dysfunction and degeneration, highlighting the potential therapeutic avenues aimed at modulating inflammation to restore neuronal homeostasis and promote neuroprotection in various neurodegenerative diseases and neurological disorders [97].
Implications of IL-23 in decreasing stemness of NSCs in development of PD:
Elevated levels of IL-23 in the brain have been implicated in diminishing the stemness of neural stem cells (NSCs), consequently affecting neurogenesis and neuronal repair processes. The influence of increased IL-23 levels on NSCs encompasses various mechanisms that contribute to the impairment of their regenerative potential [93]. One such mechanism involves the inhibition of NSC proliferation, where IL-23 activation of signaling pathways induces cell cycle arrest or apoptosis. This disruption in the balance between proliferation and differentiation reduces the pool of NSCs available for neurogenesis, thus compromising the regenerative capacity observed in neurodegenerative disorders characterized by heightened IL-23 expression [98].
Furthermore, IL-23 may skew the differentiation of NSCs towards glial cell lineages rather than neuronal lineages, promoting the formation of astrocytes and microglia. This shift in NSC differentiation not only diminishes the availability of neuronal precursors but also exacerbates neuroinflammatory processes within the brain [92]. Additionally, IL-23 interferes with the migration of NSCs towards neurogenic niches or sites of injury, hindering their recruitment to areas requiring neuronal replacement or repair. Such disruption in NSC migration impairs their ability to contribute effectively to neurogenesis, further exacerbating the decline observed in neurodegenerative conditions [99].
Moreover, IL-23 exerts a direct influence on NSC survival, either inducing apoptosis or sensitizing them to apoptotic signals. The vulnerability of NSCs to inflammatory insults is exacerbated by sustained exposure to elevated IL-23 levels, compromising their viability and regenerative potential [91]. Additionally, IL-23-mediated neuroinflammation and oxidative stress create a conducive environment for the formation and accumulation of Lewy bodies, characteristic protein aggregates associated with Parkinson's disease (PD). This interaction between IL-23 and Lewy body formation exacerbates the toxic microenvironment, further impeding NSC function and stemness. In summary, targeting IL-23 signaling pathways may offer a promising therapeutic strategy for preserving NSC stemness and promoting neuroregeneration in neurodegenerative diseases like PD, where NSC dysfunction contributes to disease progression [100].
7. IL-33 in Parkinson's Pathogenesis
Dysregulations leading to switching of neurons towards Lewy Body Buildup:
Interleukin-33 (IL-33), a member of the IL-1 cytokine family, has traditionally been recognized for its involvement in regulating immune responses and inflammation. However, recent findings indicate a potential role for IL-33 in the central nervous system (CNS) and neurodegenerative diseases like Parkinson's disease (PD) [101]. While the precise contribution of IL-33 to PD pathology remains under investigation, heightened expression of IL-33 within the brain is implicated in neuroinflammation and the formation of Lewy bodies, characteristic of PD. Elevated IL-33 levels may initiate a cascade of events within the CNS, influencing neuronal function and contributing to disease progression [110].
One mechanism through which IL-33 exerts its effects is by inducing neuroinflammation. Activation of microglia and astrocytes by IL-33 prompts the release of pro-inflammatory mediators and reactive oxygen species (ROS), fostering a neuroinflammatory milieu [102]. This chronic neuroinflammation not only damages neurons but also creates an environment conducive to the accumulation of pathological protein aggregates, such as α-synuclein, a key component of Lewy bodies [109].
Additionally, IL-33 may directly impact the expression and aggregation of α-synuclein. By promoting neuroinflammation and oxidative stress, IL-33 can facilitate the misfolding and aggregation of α-synuclein, leading to the formation of insoluble fibrils characteristic of Lewy bodies [103]. Furthermore, IL-33-mediated inhibition of protein clearance mechanisms, including autophagy and the ubiquitin-proteasome system, exacerbates the accumulation of toxic protein aggregates within neurons, further contributing to neurodegeneration [108].
Moreover, IL-33-induced oxidative stress disrupts cellular homeostasis, contributing to neuronal dysfunction and α-synuclein aggregation [104]. Additionally, dysregulation of neurotrophic support by IL-33 alters the expression and signaling of neurotrophic factors critical for neuronal survival and plasticity, exacerbating neuronal vulnerability to pathological insults. Collectively, these findings underscore the diverse role of IL-33 in promoting neuroinflammation, impairing protein clearance mechanisms, inducing oxidative stress, and dysregulating neurotrophic support, all of which may contribute to Lewy body accumulation and neuronal dysfunction in PD. However, further research is warranted to elucidate the precise mechanisms underlying IL-33-mediated neuropathology and its potential as a therapeutic target for PD [107].
Subsequent disruptions harming neuronal homeostasis and cell survival signals:
Inflammation, often mediated by cytokines such as IL-33, can profoundly disrupt neuronal homeostasis, posing significant challenges to cell survival. Among the mechanisms implicated, excitotoxicity stands out prominently [105]. IL-33 can trigger excitotoxicity by facilitating excessive glutamate release while impeding its reuptake, resulting in sustained activation of glutamate receptors and subsequent calcium influx into neurons. This disturbance in intracellular calcium dynamics activates proteases and initiates cell death pathways, ultimately compromising neuronal survival [106].
Furthermore, IL-33 instigates oxidative stress within the neuronal environment by promoting the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The overproduction of ROS/RNS overwhelms cellular antioxidant defenses, leading to oxidative damage to lipids, proteins, and DNA, thereby impairing neuronal function and viability [107]. Additionally, IL-33 contributes to mitochondrial dysfunction in neurons, disrupting mitochondrial respiration, reducing ATP production, and promoting mitochondrial permeability transition. This dysfunction exacerbates neuronal injury and cell death by depleting energy reserves, increasing ROS generation, and facilitating the release of pro-apoptotic factors [106].
Moreover, IL-33-mediated dysregulation of apoptotic signaling further compounds neuronal vulnerability. By activating apoptotic pathways within neurons and stimulating the expression of pro-apoptotic genes, IL-33 triggers the intrinsic apoptotic pathway, disrupts mitochondrial integrity, and sensitizes neurons to apoptotic stimuli [105]. Concurrently, IL-33 suppresses the expression of critical neurotrophic factors like BDNF and NGF, compromising neuronal survival and plasticity. Dysregulated synaptic function induced by IL-33 further exacerbates neuronal instability and susceptibility to injury by disrupting synaptic transmission and network activity. Collectively, these disturbances underscore the intricate interplay between inflammation, particularly mediated by IL-33, and neuronal dysfunction, highlighting potential targets for therapeutic interventions aimed at restoring neuronal homeostasis and mitigating neurodegeneration in various neurological disorders [101].
Implications of IL-33 in decreasing stemness of NSCs in development of PD:
Elevated levels of IL-33 in the brain have been implicated in diminishing the stemness of neural stem cells (NSCs), thereby impairing their ability to contribute to neurogenesis and neuronal repair processes. One notable mechanism through which this occurs is the induction of neuroinflammation by IL-33. This chronic inflammatory milieu disrupts the delicate balance of cytokines and growth factors essential for NSC proliferation and self-renewal [102, 101]. Moreover, IL-33-mediated neuroinflammation activates signaling pathways that favor the differentiation of NSCs into glial cells over neurons, further depleting the pool of neural precursors crucial for neurogenesis [103].
Furthermore, IL-33 appears to promote the differentiation of neural progenitor cells into glial lineages, particularly astrocytes, both in vitro and in vivo settings [104]. This shift towards glial differentiation can exacerbate neuroinflammation as astrocytes and microglia generated from NSCs may release pro-inflammatory mediators and induce oxidative stress, thereby contributing to the formation of Lewy bodies—a hallmark of Parkinson's disease (PD). The interplay between IL-33-mediated glial differentiation and Lewy body formation underscores the complex cascade of events that disrupt NSC function and stemness in neurodegenerative conditions [105].
Additionally, IL-33 dysregulates neurotrophic support for NSCs by altering the expression and signaling of critical factors like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) [109]. The resulting reduction in neurotrophic support compromises NSC viability and stemness, further impeding their capacity for self-renewal and differentiation. Ultimately, the cumulative effects of IL-33-induced glial differentiation, disrupted neurotrophic support, and enhanced Lewy body formation contribute to the dysregulation of neurogenesis and neuronal repair processes observed in PD. Targeting IL-33 signaling pathways may offer a promising avenue for therapeutic intervention to preserve NSC stemness and facilitate neuroregeneration in neurodegenerative disorders [101, 110].
8. IFN-γ in Parkinson's Pathogenesis:
Dysregulations leading to switching of neurons towards Lewy Body Buildup:
Interferon-gamma (IFN-γ), primarily recognized for its immunomodulatory functions, is increasingly implicated in central nervous system (CNS) processes, including neuroinflammation associated with neurodegenerative diseases like Parkinson's disease (PD) [111]. Elevated IFN-γ expression within the brain has been linked to the initiation and perpetuation of neuroinflammation, chiefly through the activation of microglia and astrocytes. These glial cells, once stimulated, release a cascade of pro-inflammatory mediators, including cytokines, chemokines, and reactive oxygen species (ROS), creating a neuroinflammatory milieu detrimental to neuronal health. This sustained neuroinflammation fosters conditions conducive to the aggregation of pathological proteins like α-synuclein, a central component of Lewy bodies characteristic of PD [1, 113].
Furthermore, IFN-γ may directly influence α-synuclein pathology by modulating its expression and aggregation. The neuroinflammatory environment induced by IFN-γ promotes oxidative stress, thereby facilitating the misfolding and aggregation of α-synuclein into insoluble fibrils characteristic of Lewy bodies [112]. Moreover, IFN-γ interferes with protein clearance mechanisms such as autophagy and the ubiquitin-proteasome system (UPS), responsible for degrading misfolded proteins like α-synuclein. The compromised clearance of these proteins leads to their accumulation within neurons, exacerbating neuronal dysfunction and contributing to Lewy body formation [119].
Additionally, IFN-γ disrupts neurotrophic support mechanisms crucial for maintaining neuronal viability and plasticity. By altering the expression and signaling of neurotrophic factors like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), IFN-γ impairs the trophic support necessary for neuronal survival and function [113]. Consequently, neurons become more susceptible to pathological insults, further exacerbating neuronal dysfunction observed in PD. Collectively, these findings highlight the diverse role of IFN-γ in promoting neuroinflammation, α-synuclein aggregation, impaired protein clearance, oxidative stress, and dysregulation of neurotrophic support, all of which contribute to Lewy body accumulation and neuronal dysfunction in PD. Nonetheless, further investigations are warranted to comprehensively understand IFN-γ's involvement in PD pathology and its potential as a therapeutic target for alleviating Lewy body pathology [118].
Subsequent disruptions harming neuronal homeostasis and cell survival signals:
Inflammation, a hallmark of many neurodegenerative diseases, including those involving the central nervous system (CNS), is deeply implicated in disrupting neuronal homeostasis [114]. The involvement of Interferon-gamma (IFN-γ) in this process has garnered increasing attention. Among its numerous actions, IFN-γ exacerbates excitotoxicity, a phenomenon characterized by excessive glutamate release leading to neuronal damage and death. By activating microglia and enhancing glutamate receptor expression on neurons, IFN-γ amplifies sensitivity to excitotoxic insults, resulting in calcium influx and the activation of cell death pathways, ultimately compromising neuronal survival [117].
Moreover, IFN-γ contributes to oxidative stress by stimulating the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) within neurons and glial cells. This excessive generation of ROS/RNS overwhelms cellular antioxidant defenses, leading to oxidative damage to lipids, proteins, and DNA, impairing neuronal function and viability [115]. Additionally, IFN-γ disrupts mitochondrial function in neurons, further exacerbating neuronal injury and cell death. By impairing mitochondrial respiration, reducing ATP production, and promoting mitochondrial permeability transition, IFN-γ instigates a cascade of events resulting in energy depletion, ROS generation, and the release of pro-apoptotic factors [116].
Furthermore, IFN-γ activates apoptotic signaling pathways within neurons, stimulating the expression of pro-apoptotic genes, activating caspases, and compromising mitochondrial integrity [116]. This intrinsic apoptotic pathway, coupled with IFN-γ-induced sensitization of neurons to apoptotic stimuli, renders them more susceptible to cell death. Additionally, IFN-γ suppresses the expression of neurotrophic factors critical for neuronal survival and function, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), further compromising neuronal viability and plasticity. Dysregulated synaptic function, induced by IFN-γ, disrupts neuronal communication and network activity, leading to synaptic dysfunction and neuronal hyperexcitability, ultimately contributing to neuronal instability and susceptibility to injury [115].
Overall, the actions of IFN-γ, alongside other inflammatory mediators, collectively disrupt neuronal homeostasis and compromise cell survival signals, precipitating neuronal dysfunction and degeneration observed in various neurodegenerative diseases and neurological disorders [117]. Therapeutic strategies targeting the modulation of inflammation and restoration of neuronal homeostasis hold promise for attenuating neuronal damage and promoting neuroprotection in such conditions [114].
Implications of IFN-γ in decreasing stemness of NSCs in development of PD:
Elevated levels of Interferon-gamma (IFN-γ) in the brain have been implicated in diminishing the stemness of neural stem cells (NSCs), consequently impeding their pivotal role in neurogenesis and neuronal repair processes, particularly in neurodegenerative diseases like Parkinson's disease (PD). This decline in NSC stemness can be attributed to several mechanisms, the first being the inhibition of NSC proliferation [118]. IFN-γ has been shown to hinder NSC proliferation by inducing cell cycle arrest or apoptosis, disrupting the delicate balance between proliferation and differentiation, and subsequently reducing the pool of stem cells available for neurogenesis, thereby impacting the regenerative capacity of the CNS [113].
Moreover, IFN-γ can promote the differentiation of NSCs into glial cells rather than neuronal lineages, exacerbating the depletion of neuronal precursors essential for neuronal regeneration and repair [119]. This shift in NSC differentiation towards glial lineages not only impedes neuronal repair mechanisms but also fosters neuroinflammatory processes, potentially exacerbating neurodegeneration. Additionally, IFN-γ dysregulates neurotrophic support for NSCs by altering the expression and signaling of critical neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), further compromising NSC viability, stemness, and their capacity for self-renewal and differentiation [112].
Furthermore, the interaction between IFN-γ and Lewy body formation, a hallmark of PD pathology, creates a toxic microenvironment detrimental to NSC function and stemness. IFN-γ-mediated neuroinflammation and oxidative stress contribute to the accumulation of Lewy bodies, containing misfolded α-synuclein, which further impairs NSC-mediated neurogenesis and repair processes [1]. In essence, the cumulative effects of IFN-γ on NSCs—such as inhibition of proliferation, promotion of glial differentiation, disruption of neurotrophic support, and enhancement of Lewy body formation—underscore its pivotal role in the dysregulation of neurogenesis and neuronal repair observed in neurodegenerative diseases like PD. Consequently, targeting IFN-γ signaling pathways holds promise as a potential therapeutic strategy to preserve NSC stemness and foster neuroregeneration in such pathological conditions [111].
9. TNF-β in Parkinson's Pathogenesis:
Dysregulations leading to switching of neurons towards Lewy Body Buildup:
TNF-β, a cytokine integral to inflammatory processes and immune responses, plays a crucial role in regulating neuroinflammation, synaptic plasticity, and neuronal survival within the brain [121]. In the context of neurodegenerative disorders, Lewy bodies stand out as abnormal protein aggregates, primarily composed of alpha-synuclein, characteristic of conditions such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Despite their prominence, the exact mechanisms driving Lewy body formation remain elusive, though neuroinflammation and protein homeostasis dysregulation are recognized as significant contributors [120].
The enhanced expression of TNF-β in the brain has emerged as a potential link to neuroinflammation, a process implicated in the pathogenesis of PD and DLB. Neuroinflammation triggers the activation of microglia and astrocytes, the central nervous system's resident immune cells, leading to the release of pro-inflammatory cytokines, including TNF-β, as part of the immune response [122]. Consequently, TNF-β can directly influence neurons by modulating synaptic transmission and plasticity while potentially inducing neuronal apoptosis under certain conditions, thus disrupting the delicate balance between neuronal survival and death, ultimately contributing to neurodegeneration [121].
Moreover, TNF-β's impact extends to the aggregation and clearance of misfolded proteins like alpha-synuclein, a key player in Lewy body formation. Studies suggest that inflammatory cytokines, including TNF-β, may exacerbate alpha-synuclein aggregation and impede its clearance pathways, culminating in Lewy body formation [123]. To sum up, the dysregulation of TNF-β expression in the brain contributes to neuroinflammation, protein homeostasis disruption, and neuronal dysfunction, all crucial elements in Lewy body diseases' pathogenesis. Further research is warranted to elucidate the specific mechanisms underlying TNF-β's role in Lewy body formation and progression, offering promising avenues for therapeutic intervention targeting neuroinflammation and cytokine signaling pathways in these debilitating neurological disorders [122].
Subsequent disruptions harming neuronal homeostasis and cell survival signals:
Inflammation, mediated in part by TNF-β, poses a significant threat to neuronal homeostasis, compromising cell survival through several mechanisms. One such mechanism is excitotoxicity, where TNF-β and other inflammatory cytokines augment the release of excitatory neurotransmitters like glutamate [124]. This excess glutamate can trigger excitotoxicity by overactivating receptors such as NMDA receptors, leading to an influx of calcium ions into neurons. This calcium influx initiates processes that damage mitochondria and activate enzymes responsible for cellular degradation, ultimately resulting in neuronal death [123].
Moreover, inflammation contributes to oxidative stress, generating reactive oxygen species (ROS) and reactive nitrogen species (RNS) that harm cellular components such as lipids, proteins, and DNA. TNF-β exacerbates oxidative stress by activating pathways within neurons that produce ROS and RNS [125]. Furthermore, inflammatory cytokines like TNF-β can disrupt neurotransmission by altering release and reuptake mechanisms, impairing synaptic communication and compromising neuronal network function, thereby promoting neuronal dysfunction and death [124].
Additionally, inflammation interferes with neurotrophic support, essential for neuronal survival, growth, and plasticity [126]. Neurotrophic factors like brain-derived neurotrophic factor (BDNF) play crucial roles in neuronal maintenance by activating intracellular signaling pathways that inhibit apoptosis and sustain synaptic function. However, TNF-β antagonizes the actions of neurotrophic factors, disrupting their signaling pathways and compromising neuronal survival signals [125].
Furthermore, inflammation, particularly through TNF-β, can activate cell death pathways such as apoptosis and necroptosis in neurons. TNF-β binds to its receptors on neuronal membranes, initiating signaling cascades that activate caspases and other proteases involved in apoptosis [124]. Additionally, TNF-β can trigger necroptotic pathways, leading to programmed necrosis characterized by cellular swelling and membrane rupture. To sum up, the dysregulation of cellular processes by inflammation, including TNF-β-mediated mechanisms, contributes to neuronal dysfunction and death, highlighting the therapeutic potential of strategies aimed at mitigating neuroinflammation and preserving neuronal homeostasis in neurodegenerative diseases characterized by chronic inflammation and neuronal loss [126].
Implications of TNF-β in decreasing stemness of NSCs in development of PD:
Elevated levels of TNF-β within the brain exert detrimental effects on the stemness of neural stem cells (NSCs), ultimately impairing neurogenesis and potentially exacerbating Lewy body pathology through interconnected mechanisms [123]. To begin with, TNF-β directly inhibits NSC proliferation by activating signaling pathways that induce cell cycle arrest or apoptosis. This inhibition reduces the pool of NSCs available for neurogenesis, compromising the brain's regenerative capacity and contributing to the accumulation of Lewy bodies and neurodegeneration [127].
In addition, TNF-β promotes the premature differentiation of NSCs into non-neuronal cell types or immature neuronal phenotypes, depleting the NSC pool and diminishing neurogenic potential [122]. This deviation from the neurogenic lineage towards the production of glial cells or aberrant neurons may underlie the pathological changes observed in neurodegenerative diseases such as Parkinson's disease and dementia with Lewy bodies [128].
Moreover, TNF-β-mediated neuroinflammation disrupts the microenvironment or neurogenic niches crucial for NSC maintenance and proliferation [121]. This inflammatory disruption alters the balance of trophic factors, cytokines, and extracellular matrix components within neurogenic niches, creating an inhospitable environment for NSC survival and proliferation. Consequently, the impairment of NSC self-renewal and stemness further diminishes their ability to generate new neurons, exacerbating brain damage associated with Lewy body diseases [129].
Furthermore, TNF-β modulates synaptic transmission and plasticity in the brain, indirectly impacting NSC function and neurogenesis. Disruptions in synaptic plasticity alter the activity-dependent regulation of NSC proliferation and differentiation, leading to aberrant neurogenic outcomes [120]. Additionally, TNF-β-induced changes in synaptic function may hinder the integration of newly generated neurons into existing neural circuits, compromising the brain's compensatory mechanisms against neuronal loss and Lewy body pathology. To sum up, targeting TNF-β and associated inflammatory pathways may represent a promising therapeutic approach to preserving NSC stemness and promoting neuroregeneration in neurodegenerative diseases characterized by Lewy body formation [130].