Nmes1 is a novel early regulator of IL-4-induced response in macrophages and regulates the wound healing capacity of the damaged intestine

The initiation of a tissue remodeling response upon damage represents a critical step for triggering resolution of inflammation and preventing the development of immune-mediated diseases. CX3CR1+ macrophages have been extensively described as having wound healing potential in the inflamed colon, making them a promising candidate for cell therapies. However, besides the extensive characterization, the molecular mechanism regulating their anti-inflammatory function is unknown. Here we show that Nmes1, encoding for Normal Mucosa of Esophagus- Specific gene 1, is a novel modulator of the early macrophage response to IL-4, and controls transcription of Gata3, Ahr and molecules associated with Wnt pathway in vitro. Additionally, by using two in vivo murine models of intestinal damage, in which an IL-4-dominated environment has distinct and opposite roles, we observed that genetic ablation of Nmes1 in the mouse leads to increased disease severity during DSS-induced colitis and prevents pathogenic/fibrotic remodeling during infection with the helminth Schistosoma mansoni. Both phenotypes observed are associated with alterations in a population of CX3CR1+ macrophages. All in all, our data indicate Nmes1 as a novel regulator of the initial wound healing response in macrophages, thus setting the basis for further investigation of NMES1 as novel target for the treatment of colon-associated inflammation.