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Tissue-resident macrophages (TRMs) are sentinel cells for maintaining tissue homeostasis and organ function. In this study, we discovered that lipopolysaccharide (LPS) administration dramatically reduced TRM populations and suppressed their self-renewal capacities in multiple organs. Using loss- and gain-of-function approaches, we define Sectm1a as a novel regulator of TRM self-renewal. Specifically, at the earlier stage of endotoxemia, Sectm1a deficiency exaggerated acute inflammation-induced reduction of TRM numbers in multiple organs by suppressing their proliferation, which was associated with more infiltrations of inflammatory monocytes/neutrophils and more serious organ damage. By contrast, administration of recombinant Sectm1a enhanced TRM populations and improved animal survival upon endotoxin challenge. Mechanistically, we identified that Sectm1a-induced upregulation in the self-renewal capacity of TRM is dependent on GITR-activated T helper cell expansion and cytokine production. Meanwhile, we found that TRMs may play an important role in protecting local vascular integrity during endotoxemia. Our study demonstrates that Sectm1a contributes to stabling TRM populations through maintaining their self-renewal capacities, which benefits the host immune response to acute inflammation. Therefore, Sectm1a may serve as a new therapeutic agent for the treatment of inflammatory diseases.

Endotoxin-triggered systemic inflammation and multiple organ dysfunction are major culprits to sepsis death. Here, we observed that the plasma levels of SECTM1 in sepsis patients were significantly lower than that in healthy donors. Similarly, the mouse homologous SECTM1A was dramatically down-regulated in multiple organs following LPS injection. Using a global SECTM1A-KO mouse model, we found that SECTM1A depletion exaggerated LPS-caused reduction of tissue-resident macrophage numbers in multi-organs by suppressing their proliferation at earlier stage, leading to more serious organ damage. By contrast, administration of recombinant SECTM1A significantly attenuated macrophage reduction and improved animal survival upon LPS challenge. Mechanistically, we discovered that SECTM1A, as a GITR ligand, contributed to maintaining self-renewal capacity of tissue-resident macrophages during endotoxemia through promoting expansions of T helper cells and releases of macrophage self-renewal cytokines. Our study suggests that SECTM1A is essential for macrophage self-renewal and may serve as a new therapeutic agent for sepsis.