SECTM1A Positively Regulates Tissue-Resident Macrophage Self-Renewal Capacity by Boosting T Helper Cells in Mice During Endotoxemia

Abstract

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.