Iron overload induces intestinal macrophage dysfunction and promotes enteric infection in hemochromatosis 2255857

Abstract Introduction Hemochromatosis is an iron overload (IO) disorder that causes multi-organ damage, immune dysfunction, and increased susceptibility to enteric infections. There have been numerous case studies reporting septic-like outcomes for hemochromatosis patients infected with Gram-negative, enteric Yersiniae. However, the impact of hemochromatosis on intestinal immunity and its role in exacerbating infection remains unclear. Methods Our lab has established a mouse model in which C57BL/6 mice are fed a high-iron diet for four weeks, resulting in elevated serum iron, transferrin saturation, ferritin levels, tissue iron deposition, and heightened susceptibility to Yersinia enterocolitica (Ye) infection. Results During intestinal inflammation, the monocyte-macrophage differentiation process is stalled, leading to the accumulation of monocytes and immature intestinal macrophages (IMs). Immature IMs fail to differentiate into highly phagocytic, reparative, mature IMs seen at homeostasis, but instead remain highly responsive to pattern recognition receptor stimulation and are potent producers of inflammatory cytokines. I have observed that increasing iron levels elevate CCL2 levels in the serum and intestine, leading to increased monocyte mobilization and intestinal infiltration. In IO mice, the intestine contains more inflammatory monocytes and immature IMs, along with elevated levels of TNF-a, IL-1B, and IL-6 cytokines, which are known to be produced by these cell types. This phenotype is dependent on both high iron and CCR2 signaling and is exacerbated following Ye infection. Conclusion My data indicate that the CCL2/CCR2 axis has a detrimental role during Ye infection in IO mice, as disruption of this axis significantly improves animal survival. I hypothesize that IO-induced inflammation and CCL2/CCR2 signaling stalls the monocyte-macrophage differentiation process in the intestine, resulting in the accumulation of immature, inflammatory IMs that contribute to mortality during Ye infection. Funding Source NIAID R01AI162670 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)