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, LYVE1^hi TIM4(−) and LYVE1^lo/− TIM4(−) subsets, alongside embryonically derived LYVE1^hi TIM4(+) macrophages. LYVE1^lo/− TIM4(−) macrophages, but not LYVE1^hi 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.