Obesity is a major risk factor for psoriasis (6). Previous work has indicated that disease severity of psoriasis relates to heightened NETs formation, but the regulatory roles and internal mechanism of NETs in psoriasis still remain elusive (25, 29). Herein, we delineated that increased NETs induced by abnormal fatty acid metabolism remodulated skin immune microenvironment and it was essential for obesity-exacerbated psoriasis. Elevated SFAs in obese individuals promoted release of NETs through TLR4–MD2/ROS signaling pathway, which further amplified type 17 immune responses. Moreover, our results provided evidence that SFAs drove the abrogation of anti-IL17A therapeutic effect in psoriasis with lipid metabolism disorder and that NETs inhibition combined with anti-IL17A treatment could reverse this phenomenon. Therefore, we document that NETs inhibition may serve as a potential therapeutic avenue in defined psoriatic settings with lipid metabolism disorder clinically (Fig. 7).
The existence of NETs in skin lesions and blood of both psoriasis patients and imiquimod-induced psoriasis-like mice has been addressed (25, 29, 30). Here, we found that systemic NETs and localized cutaneous NETs in both obese psoriasis patients and IMQ-induced psoriasis-like mice were significantly higher than lean subjects. Inhibition of NETs significantly alleviated the inflammation in obesity-aggravated psoriasis but failed to influence the pathogenesis of imiquimod alone. In line with our study, NETs inhibition ameliorates skin inflammation in psoriasis exacerbated by IL-36 receptor antagonist deficiency and fungi-aggravated psoriasis but exhibits no significant impact on mice treated by imiquimod alone (39, 40). Moreover, studies have reported that NETs directly promote psoriasis exacerbation by mediating keratinocytes activation, plasmacytoid dendritic cells stimulation, and release of IL-17A (25, 29, 30, 41, 42). However, little is known about the precise mechanism regulating the production of NETs in psoriasis. According to our results, changes in fatty acid metabolism led to the increase of NETs generation. Others have reported that the release of keratinocyte exosomes activates neutrophils and induces NETs formation (43). Moreover, the self-propagating vicious cycle mediated by RNA and LL37 via TLRs recognition and NETs formation contributes to chronic inflammation in psoriasis (44). Thus, it’s plausible that NETs formation is vital for the exacerbation of psoriatic inflammation induced by obesity.
According to our results, neutrophils from obese subjects are more prone to generate NETs. Other investigators have shown similar results that obesity/lipid metabolism disorder leads to greater NETs formation in influenza pneumonia mouse model, vascular dysfunction mouse model, the STAM mouse model, and ApoE-deficient mice (20, 22, 45–47). However, the exact mechanism of obesity/lipid metabolism disorder promoting NETs generation awaits further study. Metabolic pathways that regulate glycolysis and energy supply have been proved to be tightly linked to the capacity of neutrophils to produce NETs (48–50). Moreover, SFAs such as PA and SA are among the most enriched FFAs in both serum and skin from HFD-fed mice and SFAs have been regarded as major risk factors for the amplification of skin inflammation (14, 15). Thus, we focused on SFAs as a contributor for augmented NETs formation in obesity-exacerbated psoriasis. Our study indicates that NETs have already proceeded in obesity subjects and SFAs promote NETs production in a dose-dependent manner.
Mechanistically, our data reveal that SFA-induced TLR4-MD2 complex formation further promote NOX-derived ROS, which leads to NETs generation in obesity-exacerbated psoriasis. SFAs directly stimulate inflammatory gene expression by way of TLR4 signaling, while MUFAs and PUFAs fails to activate TLR4 signaling (51, 52). In hepatic macrophages of an HFD-induced hepatic steatosis mouse model, endocytosis of palmitate/TLR4–MD2 complex generates NOX2-mediated ROS (37). In obesity-associated myocardial injury, saturated palmitic acid direct binds to TLR4 accessory protein MD2 and activates downstream inflammatory responses (38). Considering that ROS generation is fundamental for NET formation, we conclude that SFAs promote NETs production through TLR4-MD2/ROS signaling pathway (53). Further studies need to determine whether other abnormal lipid metabolites are engaged in obesity-promoted NETs generation.
Our results reconfirmed the known role for NETs in promoting IL-17/Th17 responses (54, 55). With well-documented proinflammatory functions, neutrophils externalize IL-17A-decorated NETs in many diseases such as psoriasis, ankylosing spondylitis, pulmonary fibrosis, asthma, Alzheimer’s disease, and acute myocardial infarction (29, 56–60). Previous studies have also illustrated the indirect amplification of Th17 responses by NETs through macrophages, dendritic cells, and monocytes (22, 61–63). In addition, NETs directly prime T cells by lowering their activation threshold and promotes Th17 differentiation, which is mediated through a TLR2/MyD88-dependent pathway (24, 64, 65). Interestingly, in our study, other than the augmentation of Th17 responses by NETs, we propose that NETs induce innate IL-17 production from γδT cells, which even seems to play a more important role in obesity-exacerbated psoriasis than Th17-derived IL-17. Furthermore, IL-17A induces recruitment of neutrophils and enhances NETs generation (66–68). Thus, a corollary to these findings implies that NETs formation has a positive feedback function on the IL-17A driven dynamic inflammation, which further elicits NETs formation and promotes immunopathology in obesity-exacerbated psoriasis. However, the putative mechanism about interactions between NETs and IL-17A-producing T cells remains to be investigated.
Clinically, a weight-based approach to secukinumab and ustekinumab has been proposed, indicating that higher doses of biologics may be required for psoriasis patients with greater bodyweight to optimize their efficacy (11, 13). As many obese psoriasis patients show poor responses to immunotherapy and carry an intolerable psychological and economic burden, it is vital to identify biomarkers for the evaluation of therapeutic efficacy and to establish new strategies for combined immunotherapy (11, 12, 69). However, little is known about the precise mechanism of decreased responses resulting from lipid metabolism disorder. Our research identifies SFAs as a major hindrance for anti-IL17A treatment in psoriatic mice with severe symptoms and remarkable local pathological changes. Incredibly, NETs inhibitor combined with anti-IL17A treatment could improve the decreased response in the light of ameliorated symptoms and pathological changes. Thus, our results suggest an intriguing possibility that NETs inhibitors combined with anti-IL17A could be a promising option for psoriasis patients with lipid metabolism disorders. However, although we identified SFAs as the major stimulus for augmented skin inflammation, the effects of unsaturated fatty acids were not investigated and their clear functional differences were not clarified. And further clinical investigation is warranted to learn whether NETs inhibition combined with anti-IL17A treatment can reverse the severe condition of obese psoriasis patients.
In summary, we highlight the importance of SFAs-induced NETs for dermatologic conditions with overnutrition status. Mechanistically, TLR4-MD2/ROS signaling pathway is critical for SFAs-induced NETs generation. In addition, our research suggests a feed-forward loop in which NETs trigger IL-17 immunity, evolving neutrophils from terminal effectors to complex mediators. Thus, our study reveals that breaking the vicious cycle with NETs inhibitors could be a novel and promising candidate for psoriasis patients with obesity, especially those who show poor responses to various biological agents clinically.