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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.

Microvesicles (MV) are membranous extra cellular vesicles derived from various cells following cell activation or apoptosis. MVs are typically defined as being from 0.1 to 1 µ in size. There have been several reports of biologically active MVs in the blood in certain clinical conditions. The goal of this study was to examine the effects of thermal injury plus sepsis on the number and type of MVs released from leukocytes. C57BL/J mice received 15% total body surface area burn followed by infection with Pseudomonas aeruginosa. At times post injury the blood and bone marrow were examined for MV expressing CD11b, CD19, CD34, CD41, and CD117 using flow cytometry. Generally,the absolute number of MV in the blood dropped following, however, the percentage of the various cell types changed. The percentage of CD11b, 34, and 42 increase slightly following burns but significantly following burn/infection.The absolute numbers of all MV dropped with the exception of CD 19 which increased both in percentage and absolute number in the burn group but not the burned/infected group. The absolute number of CD117+ MV increased significantly in the burn/infected group.The bone marrow remained relative stable with a slight increase in CD117+ MV. These data indicate that the pattern of MVs production changes following burn injury and burn infection. Because the number of CD34+ MV did not increase it would appear that the large increase in CD117+ MV was due to increase in common myeloid progenitors.