Cell-intrinsic IL4R alpha independence of large intestinal RELMα+ Ym1+ macrophages

The balance of pro-inflammatory and anti-inflammatory macrophages is critically important in enabling the development and resolution of inflammatory responses. Anti-inflammatory macrophages have been shown to be activated by IL4 and/or IL13 via the IL4Rα. In the context of type 2 immunity, anti-inflammatory macrophages have been defined by the expression of the signature markers RELMα, CD206 and Ym1, associated with activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, many of which feature unbalanced macrophage activation states, little is known about how large intestinal macrophages are activated. Here, we address this important knowledge gap by using a Trichuris muris infection model of resolving type 2 intestinal inflammation, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. These models allowed us to interrogate the role of IL4/IL13 in macrophage activation driven by inflammation of the large intestine. We make the unexpected finding that education of large intestinal macrophages towards a RELMα and Ym1 expressing cell type during type 2 inflammation, does not require IL4Rα expression on macrophages. Thus, upregulation of RELMα and Ym1 post infection is independent of macrophage IL4Rα expression. Further, this independence is maintained even when the mice are treated with anti-IFNγ antibody to create a strongly polarised Th2 environment. In contrast to RELMα and Ym1, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These data challenge existing paradigms, evidencing that expression of RELMα and Ym1 by macrophages, typically regarded as having anti-inflammatory functions, do not always rely on IL4/IL13. ### Competing Interest Statement The authors have declared no competing interest.