Mesenteric macrophage-monocyte circuit controls systemic inflammation during enteric bacterial infection

Although the gut mesentery is anatomically linked to the intestines, the roles of mesentery-resident macrophages and mesentery-recruited monocytes, particularly in gut inflammation, remain poorly defined. Here, we show that mesenteric macrophage-monocyte interactions limit systemic infection during Salmonella Typhimurium (STm)-induced gut inflammation. Using Ccr2-deficient mice and fate-mapping approaches, we identified two distinct granulocyte-monocyte progenitor (GMP)-derived macrophage populations in the gut mesentery, LYVE1hi TIM4(-) and LYVE1lo/- TIM4(-) subsets, alongside embryonically derived LYVE1hi TIM4(+) macrophages. LYVE1lo/- TIM4(-) macrophages, but not LYVE1hi macrophages, removed excessively recruited neutrophils during STm infection, whereas newly mesentery-recruited monocytes were the primary source of inflammatory cytokines. Moreover, depletion of mesentery-resident macrophages in mice lacking Csf1 in serous stromal cells resulted in excessive recruitment of GMP-derived monocytes accompanied by elevated expression of inflammatory cytokines, thereby accelerating mortality during STm infection. Together, our findings reveal that the mesenteric macrophage-monocyte circuit buffers the escalation of gut infection into systemic inflammation.