Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis

Wu, Xunyao; Li, Ketian; Yang, Huaxia; Yang, Bo; Lü, Xin; Zhao, Lu; Fei, Yun-yun; Chen, Hua; Wang, Li; Li, Jing; Peng, Lixin; Zheng, Wenjie; Hou, Yong; Jiang, Ying; Shi, Qun; Zhang, Wen; Zhang, Fengchun; Zhang, Jianmin; Huang, Bo; He, Wei; Zhang, Xuan

doi:10.1016/j.jaut.2019.102336

Cited by 106 publications

(82 citation statements)

References 16 publications

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“…The emergence of the complement-associated inflammasome signaling pathway after ART initiation may contribute to TB-IRIS immunopathology, since it correlates with IL-1β and IL-18 plasma levels and its decay is associated with dampening in IRIS-related symptoms promoted by anti-inflammatory therapy. Consistently, crosstalk between MAC and inflammasome activation was recently reported as the mechanism underlying inflammation during complement-mediated autoinflammatory diseases like paroxysmal nocturnal hemoglobinuria [73] and rheumatoid arthritis [74]. Therefore, our findings suggest the use of drugs designed to inhibit either the complement cascade or the NLRP3/ASC/caspase-1/4/5 molecules as a potential new therapeutic approach to treat TB-IRIS.…”

Section: Plos Pathogenssupporting

confidence: 88%

Classical complement and inflammasome activation converge in CD14highCD16- monocytes in HIV associated TB-immune reconstitution inflammatory syndrome

et al. 2021

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Inflammasome-derived cytokines, IL-1β and IL-18, and complement cascade have been independently implicated in the pathogenesis of tuberculosis (TB)-immune reconstitution inflammatory syndrome (TB-IRIS), a complication affecting HIV+ individuals starting antiretroviral therapy (ART). Although sublytic deposition of the membrane attack complex (MAC) has been shown to promote NLRP3 inflammasome activation, it is unknown whether these pathways may cooperatively contribute to TB-IRIS. To evaluate the activation of inflammasome, peripheral blood mononuclear cells (PBMCs) from HIV-TB co-infected patients prior to ART and at the IRIS or equivalent timepoint were incubated with a probe used to assess active caspase-1/4/5 followed by screening of ASC (apoptosis-associated speck-like protein containing a CARD domain) specks as a readout of inflammasome activation by imaging flow cytometry. We found higher numbers of monocytes showing spontaneous caspase-1/4/5+ASC-speck formation in TB-IRIS compared to TB non-IRIS patients. Moreover, numbers of caspase-1/4/5+ASC-speck+ monocytes positively correlated with IL-1β/IL-18 plasma levels. Besides increased systemic levels of C1q and C5a, TB-IRIS patients also showed elevated C1q and C3 deposition on monocyte cell surface, suggesting aberrant classical complement activation. A clustering tSNE analysis revealed TB-IRIS patients are enriched in a CD14highCD16- monocyte population that undergoes MAC deposition and caspase-1/4/5 activation compared to TB non-IRIS patients, suggesting complement-associated inflammasome activation during IRIS events. Accordingly, PBMCs from patients were more sensitive to ex-vivo complement-mediated IL-1β secretion than healthy control cells in a NLRP3-dependent manner. Therefore, our data suggest complement-associated inflammasome activation may fuel the dysregulated TB-IRIS systemic inflammatory cascade and targeting this pathway may represent a novel therapeutic approach for IRIS or related inflammatory syndromes.

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Section: Plos Pathogenssupporting

confidence: 88%

Classical complement and inflammasome activation converge in CD14highCD16- monocytes in HIV associated TB-immune reconstitution inflammatory syndrome

et al. 2021

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“…Pyroptosis has been reported to act primarily on phagocytic cells, macrophages, monocytes and dendritic cells ( Miles et al, 2013 ; de Almeida et al, 2015 ; Martinet et al, 2019 ), as well as various other cell types in inflammatory diseases such as T cells ( Luo et al, 2019 ). Previous studies have shown an enhanced expression of GSDMD in the serum of patients with rheumatoid arthritis (RA) and emphasized pyroptosis in association with RA ( Wu et al, 2020 ). Moreover, Wang Y. et al (2019) found that chemical GSDMD-related pyroptosis of tubular cells in diabetic kidney disease is dependent on the TLR4/NF-κB signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Andrade-Oliveira Salvianolic Acid B Modulates Caspase-1–Mediated Pyroptosis in Renal Ischemia-Reperfusion Injury via Nrf2 Pathway

et al. 2020

Front. Pharmacol.

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Acute kidney injury (AKI) is a serious disease characterized by a rapid decline in kidney function. Oxidative stress is the primary pathogenesis of AKI. Salvianolic acid B (SalB), a water-soluble compound extracted from Salvia miltiorrhiza , possesses a potent antioxidant activity. Here, we investigated the protective effect of SalB against renal ischemia-reperfusion injury (I/R) in mice. Briefly, by analyzing renal function, oxidative stress markers and inflammatory biomarkers, we found that SalB could improve kidney damage, reduce oxidative stress and inflammatory factor levels. Interestingly, the expression of the NLR family pyrin domain-containing 3 (NLRP3), caspase-1, pyroptosis related proteins gasdermin D (GSDMD) and interleukin (IL)-1β, which were significantly upregulated in the kidney tissues of I/R group, was effectively reversed by SalB. Meanwhile, renal tubular epithelial cells hypoxia and reoxygenation model was used to explore pyroptosis of caspase-1-dependent. Further mechanism study showed that the SalB pretreatment could promote the increase of nuclear factor erythroid-2 related factor 2 (Nrf2) nuclear accumulation, which significantly suppressed oxidative stress, proinflammatory cytokines, NLRP3 inflammasome activation and pyroptosis. These results indicate that SalB can inhibit caspase-1/GSDMD-mediated pyroptosis by activating Nrf2/NLRP3 signaling pathway, resulting in alleviating I/R injury in mice.

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“…A recent study from Zhang and his team demonstrated that complement C1q synergises with pentraxin 3 (PTX3) in promoting NLRP3 overactivation, ultimately resulting in GSDMD‐mediated monocyte pyroptosis and excessive inflammatory cytokine release in RA. Additionally, the release of inflammatory cytokines, such as IL‐6, in turn, drives PTX3 plus C1q‐induced GSDMD‐dependent monocyte pyroptosis in a positive feedback 86 . These findings further explore the pathogenic effects of gasdermin family on RA, suggesting a potential novel therapeutic strategy by targeting pyroptosis in RA.…”

Section: Role Of the Gasdermin Family In Inflammatory Diseasesmentioning

confidence: 72%

“…Additionally, the release of inflammatory cytokines, such as IL-6, in turn, drives PTX3 plus C1q-induced GSDMDdependent monocyte pyroptosis in a positive feedback. 86 These findings further explore the pathogenic effects of gasdermin family on RA, suggesting a potential novel therapeutic strategy by targeting pyroptosis in RA.…”

Section: Rheumatoid Arthritismentioning

confidence: 80%

Emerging insights on the role of gasdermins in infection and inflammatory diseases

Tang

Zheng

et al. 2020

Clin & Trans Imm

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The gasdermins, family of pore-forming proteins, are emerging key regulators of infection, autoinflammation and antitumor immunity. Multiple studies have recently characterised their crucial roles in driving pyroptosis, a lytic pro-inflammatory type of cell death. Additionally, gasdermins also act as key effectors of NETosis, secondary necrosis and apoptosis. In this review, we will address current understanding of the mechanisms of gasdermin activation and further describe the protective and detrimental roles of gasdermins in host defence and autoinflammatory diseases. These data suggest that gasdermins play a prominent role in innate immunity and autoinflammatory disorders, thereby providing potential new therapeutic avenues for the treatment of infection and autoimmune disease.

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Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis

Cited by 106 publications

References 16 publications

Classical complement and inflammasome activation converge in CD14highCD16- monocytes in HIV associated TB-immune reconstitution inflammatory syndrome

Classical complement and inflammasome activation converge in CD14highCD16- monocytes in HIV associated TB-immune reconstitution inflammatory syndrome

Andrade-Oliveira Salvianolic Acid B Modulates Caspase-1–Mediated Pyroptosis in Renal Ischemia-Reperfusion Injury via Nrf2 Pathway

Emerging insights on the role of gasdermins in infection and inflammatory diseases

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