Abstract

Resident macrophages (møs) from different tissues are highly heterogeneous in terms of their functions and origins. Intestinal møs are one of the largest populations in the body and have several characteristic features, including expression of high levels of MHCII and CX3CR1, constitutive production of IL10 and TNFa and avid phagocytic activity. However they are refractory to stimuli such as TLR ligands. We have shown that adult intestinal møs are derived from circulating Ly6Chi monocytes that acquire the properties of the resident cells in the mucosa. However the mechanisms responsible for this local differentiation process are unknown. By comparing their transcriptome with monocyte- and embryonically derived møs from other tissues, here we identify a genetic signature of resident intestinal møs and validated it by Q-PCR and FACS. Soon after entry into the intestine, maturing møs become genetically distinct, even from møs in other tissues that are replenished by monocytes, such as the dermis. Many of the selectively expressed molecules are involved in tissue remodeling and in uptake of apoptotic cells, including avβ5 integrin, metalloproteases 2, 9 & 14, C1Q and CD36. Several are TGFβ inducible genes and although intestinal møs numbers are normal in CD11c-cre-TGFβR1fl/fl mice, their gene signature is altered and they show reduced expression of IL10 and CX3CR1. In parallel, chimeric mice lacking TGFβR signaling only on møs show evidence of increased inflammatory monocyte recruitment. Thus TGFβR signaling is critical for tissue specific adaptation of intestinal møs, driving the differentiation of monocytes into møs with homeostatic and anti-inflammatory functions.