PDF(Pubmed)
Abstract：
Noncanonical pyroptosis is triggered by Caspase 4/5/11, which cleaves Gasdermin D (GSDMD), leading to cell lysis. While GSDMD has been studied previously in systemic lupus erythematosus (SLE), the role of pyroptosis in SLE pathogenesis remains unclear and contentious, with limited understanding of Caspase 11-mediated pyroptosis in this condition. In this study, we explored the level of Caspase 11-mediated pyroptosis in SLE, identifying both the upstream pathways and the interaction between pyroptosis and adaptive immune responses. We observed increased Caspase 5/11 and GSDMD-dependent pyroptosis in the macrophages/monocytes of both lupus patients and mice. We identified serum lipopolysaccharide (LPS), released from the gut due to a compromised gut barrier, as the signal that triggers Caspase 11 activation in MRL/lpr mice. We further discovered that pyroptotic macrophages promote the differentiation of mature B cells independently of T cells. Additionally, inhibiting Caspase 11 and preventing LPS leakage proved effective in improving lupus symptoms in MRL/lpr mice. These findings suggest that elevated serum LPS, resulting from a damaged gut barrier, induces Caspase 11/GSDMD-mediated pyroptosis, which in turn promotes B cell differentiation and enhances autoimmune responses in SLE. Thus, targeting Caspase 11 could be a viable therapeutic strategy for SLE.
摘要：
非规范的焦亡是由Caspase4/5/11触发的，它切割GasderminD（GSDMD），导致细胞裂解。虽然GSDMD先前已在系统性红斑狼疮（SLE）中进行了研究，焦凋亡在SLE发病机制中的作用尚不清楚，存在争议，在这种情况下，对Caspase11介导的焦亡的了解有限。在这项研究中,我们探讨了SLE中Caspase11介导的焦亡水平，确定上游途径以及焦亡和适应性免疫反应之间的相互作用。我们在狼疮患者和小鼠的巨噬细胞/单核细胞中观察到Caspase5/11和GSDMD依赖性焦亡增加。我们鉴定了血清脂多糖（LPS），由于肠道屏障受损而从肠道释放，作为触发MRL/lpr小鼠中Caspase11激活的信号。我们进一步发现，促性腺激素巨噬细胞独立于T细胞促进成熟B细胞的分化。此外,在MRL/lpr小鼠中，抑制Caspase11和防止LPS渗漏证明可有效改善狼疮症状。这些结果表明，血清LPS升高，由于肠道屏障受损，诱导Caspase11/GSDMD介导的焦亡，进而促进B细胞分化并增强SLE中的自身免疫反应。因此，靶向Caspase11可能是SLE的可行治疗策略.
