About 5–10% of strokes are subarachnoid hemorrhages, a form of stroke in which a blood vessel at the base or surface of the brain bursts [27], causing blood to flow into the subarachnoid space with concomitant clinical symptoms [28]. The most common cause of SAH (85%) is an intracranial aneurysm; other causes include cerebral arteriovenous anomalies, anomalous vascular retinopathy of the base of the brain, dural arteriovenous fistulae, entrapment aneurysms, vasculitis, thrombosis in the intracranial venous system, intratumoral tumors, blood disorders, coagulopathies, and complications from anticoagulants, among others[29–31]. For some of the patients, the cause is uncertain. Subarachnoid hemorrhage (SAH) caused by ruptured aneurysm is mainly located at the bifurcation of the cerebral basal arteries, particularly near the Willis circle[32, 33]. Even if the patient survives, they may still have lasting neurological impairments, which can have a significant negative impact on their quality of life. To this day, the mechanisms leading to aneurysm rupture remain highly complex. The main contributing factors include aneurysm size larger than 7 millimeters, presence of inflammation, genetic syndromes, and hypertension[3, 34]. Studies have shown that there are five types of gut microbes that are closely related to SAH[35]. However, in this study, only two gut microbiome-related pathways were summarized through meta-analysis and were associated with subarachnoid hemorrhage (Fig. 2). Among them, the gut bacterial pathway abundance pyridoxal-5-phosphate biosynthesis I may be considered a risk factor for SAH (OR > 1). When the level of pyridoxal-5-phosphate biosynthesis I increases, it will promote the development of SAH. The MR Egger analysis showed that there was no significant level of pleiotropy in pyridoxal 5-phosphate biosynthatis I (Fig. 2). That indicates the credibility of the results. The gut bacterial pathway ambiguity glucose biosynthesis I may serve as a protective factor for SAH. The results of the meta-analysis indicate that OR = 0.68, indicating that the higher the glucose biosynthesis I, the lower the risk of SAH. The results of MR Egger also indicate that there is currently no significant level of pleiotropy.
Inflammation is primarily associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease[36]. In the pathogenesis of SAH, inflammation plays a crucial role, with studies showing that there is neuronal damage caused by both cellular and molecular inflammation in the subarachnoid space[37]. Congenital immune responses may promote a series of inward-outward inflammatory reactions in the subarachnoid space. Experts have proposed that postoperative inflammation in patients with hemorrhagic aneurysms can increase the probability of adverse clinical events, especially due to elevated levels of inflammatory factors such as IL-6 and TNF-α[37, 38]. Furthermore, in brain injury and the inflammatory mechanisms associated with brain injury, high levels of IL-6 and TNF-α in the cortex are associated with post-SAH red blood cell lysis[39].
The rupture of aneurysms causes SAH, which promotes the increase in neutrophils and inflammatory cytokines IL-6 in the brain. At the same time, an increase in IL-6 is also associated with local and periphery inflammation[40, 41]. Infiltration of inflammatory immune cells provides a potential target for treatment of SAH patients[40]. It is widely believed that IL-6 is a contributor to brain damage, potentially leading to adverse clinical outcomes with poor prognosis[42]. In the context of neuroinflammation, IL-6 is significantly associated with EBI following aneurysmal SAH. In addition, soluble gp130 (sgp130) is an IL-6 antagonist that can inhibit the production of IL-6. Conversely, IL-6 is an agonist receptor for the IL-6R. When SAH occurs, gp130 can limit the elevation of IL-6. However, when gp130 levels decline, it may contribute to cerebrovascular spasm and corresponding neuroinflammation damage[43]. Some studies have shown that recently marketed IL-6 signaling inhibitors are full-length gp130. Other studies have confirmed that proteins related to the innate immune system will be activated by the IL-6 signal and tissue-specific sgp130[44]. Some immune cells and corresponding chemokines associated with sgp130 can inhibit neuroinflammation[45, 46]. There is evidence to suggest that the main sgp130 isoform specifically binds to the IL-6/IL-6R complex, thereby inhibiting its proinflammatory function[47]. In addition, there is a related mechanism where the thioredoxin-interacting protein (TXNIP) interacts with the NLRP3 inflammasome containing the pyrin domain of the NOD-like receptor family, promoting the generation of interleukin IL-1β. The NLRP3 inflammasome belongs to the innate immune system. The NLRP3 inflammasome is essentially a complex involved in the mechanism of innate immune response, but under conditions of runaway activation, the NLRP3 inflammasome will abnormally activate the immune system and inflammation, typical examples being abnormal metabolism of mitochondria and accumulation of ROS[48]. Some studies have shown that the NLRP3 inflammasome may promote the generation of IL-1β and IL-18, which will exacerbate the post-SAH inflammation response and promote the progression of EBI[49, 50]. By inhibiting the NLRP3-related inflammatory response, it is possible to inhibit neuronal inflammation and promote recovery of neurological function[51]. Intracellular activation of NLRP3 leads to accumulation of ROS, which activates inflammasome[52]. Some strong antioxidants, such as melatonin, can inhibit EBI and inflammation after SAH[53], thereby improving the prognosis of SAH[51]. Melatonin also suppresses the levels of inflammatory cytokines such as IL-1β, IL-6 and TNF-α. These inflammatory signaling molecules promote progression of brain diseases after SAH[54]. There are multiple immune and inflammatory processes that occur in different segments after SAH, which may be related to the production of inflammatory cytokines and immunoregulatory molecules. In our study, we discovered a new inflammase-related molecule, the Urokinase type plasminogen activator. MR and meta-analysis confirmed that the Urokinase type plasminogen activator will affect SAH, and increasing the Urokinase type plasminogen activator will promote the progression of SAH, indicating that this will be a new therapeutic target.
More and more studies have confirmed the role of inflammation in subarachnoid hemorrhage (SAH). However, due to its complex activation mechanism and vast immune system, the exact pathway of inflammation in SAH still needs further verification. Research suggests that the high incidence of bacterial pneumonia in asymptomatic aneurysmal SAH patients may be attributed to impaired immune response and decreased T cell count. Clinical studies have shown that some cases of secondary SAH may be mediated by immune-related diseases, especially immune hyperactivity disorders such as autoimmune hemolytic anemia, Crohn's disease, and hyperthyroidism[55]. Some clinical studies have also shown that SAH patients after surgical treatment may experience short-term immune dysfunction. Inhibition of certain immune cells, such as CD4+, CD8 + T cells, natural killer cells (NKs), and regulatory T cells (Tregs), will lead to worse prognosis in patients[56]. One clinical study has shown that injection of low-dose interleukin-2 (IL-2) in SAH patients can significantly inhibit the differentiation of Treg cells, thereby suppressing post-SAH neuroinflammation. Some pathological studies have indicated that reducing pro-inflammatory factors and neutrophils in the blood can promote neurological function recovery[57]. Research has shown that regulatory T cells have two main functions: inhibiting the proliferation of normal T cells and releasing cytokines[58]. Immunosuppressive regulatory T cells can inhibit pro-inflammatory factors (tumor necrosis factor-alpha and interferon-gamma) and promote the generation of anti-inflammatory factors (interleukin-10) to suppress inflammatory responses[59–61]. In this study, meta-analysis of MR results revealed that CD80 on CD62L + plasmacytoid Dendritic Cell, CD80 on plasmacytoid Dendritic Cell, CD123 on CD62L + plasmacytoid Dendritic Cell and SSC-A on plasmacytoid Dendritic Cell was positively correlated with SAH. This suggests that these four types of inflammatory cells may exacerbate the symptoms of SAH (OR > 1, Fig. 4 and Fig. 5). No significant statistical differences were found in the meta-analysis of immune cells.