Data_Sheet_1_Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function.docx

Ly6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6Chi monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6Chi monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6Chi monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6Chi monocytes. In consistence with these results, COMMD10-deficiency in Ly6Chi monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6Chi monocytes and their corresponding human CD14hi monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6Chi monocyte inflammasome activity during systemic inflammation and IBD.

Ly6Chi单核细胞组织浸润在调节败血症和炎症性肠病（IBD）期间的局部炎症、细菌清除和消退过程中发挥着重要作用。然而，调控其活性的免疫调节通路尚不甚明了。COMMD家族蛋白正逐渐成为炎症期间信号传导和蛋白质运输事件的关键调节因子，但COMMD10在调控Ly6Chi单核细胞驱动炎症中的具体作用尚不明确。本研究报告指出，COMMD10在LPS诱导的系统炎症模型中抑制了Ly6Chi单核细胞的经典和非经典炎症小体活性。相应地，其在髓系细胞中的缺乏，而非组织驻留巨噬细胞中的缺乏，导致了Ly6Chi单核细胞肝脏和结肠浸润增加、全身性细胞因子风暴升高、肝脏和结肠中caspase-1和-11的激活增加，以及全身性IL-1β产生增加，特别是在LPS挑战的循环Ly6Chi单核细胞中。这些炎症表现伴随着肠道屏障功能的损害，随后细菌传播至肠系膜淋巴结和肝脏，导致死亡率增加。通过诱导性清除COMMD10缺陷的Ly6Chi单核细胞，可以改善炎症小体活性和肠道屏障泄漏。与这些结果一致，与肠道驻留的固有层巨噬细胞相比，Ly6Chi单核细胞中的COMMD10缺乏导致了IL-1β产生增加和结肠炎症加剧，在DSS诱导的结肠炎模型中。最后，COMMD10在DSS诱导的结肠炎小鼠的Ly6Chi单核细胞及其对应的人类CD14hi单核细胞中表达降低，这些细胞分别来自结肠炎患者。综上所述，这些研究结果突出了COMMD10在全身炎症和IBD期间作为Ly6Chi单核细胞炎症小体活性的负调节因子的作用。