Trichuris muris infection drives cell-intrinsic IL4R alpha independent colonic RELMα plus macrophages

Author summary Infection of mice with Trichuris muris, a whipworm parasite results in inflammation of the large intestine. Inflammation is temporary; once the parasite has been cleared, damage to the intestinal tissue heals. During inflammation white blood cells move in to the gut tissue. These cells are dominated by a cell type called the macrophage. Macrophages which accumulate in the intestine post-infection express a protein called RELM alpha. These RELM alpha-expressing macrophages are thought to help resolve inflammation and have traditionally been associated with IL-4 and IL-13-driven activation. We set out to determine whether the macrophages which emerge during T. muris infection need to respond to IL-4 and/or IL-13 in order to express RELM alpha. We did this by creating a transgenic mouse where the common IL4R alpha chain of the IL-4 and IL-13 receptor was absent from macrophages. To our surprise, macrophages were able to express RELM alpha regardless of whether the macrophage could or could not respond to IL-14/IL-13. This new knowledge is important as in some inflammatory conditions, treatments seeking to encourage alternatively activated macrophages have been proposed. Such treatments require an understanding of both the important and the redundant signals as well as recognition that activating signals may be disparate in different tissue environments. The intestinal nematode parasite Trichuris muris dwells in the caecum and proximal colon driving an acute resolving intestinal inflammation dominated by the presence of macrophages. Notably, these macrophages are characterised by their expression of RELM alpha during the resolution phase of the infection. The RELM alpha+ macrophage phenotype associates with the presence of alternatively activated macrophages and work in other model systems has demonstrated that the balance of classically and alternatively activated macrophages is critically important in enabling the resolution of inflammation. Moreover, in the context of type 2 immunity, RELM alpha+ alternatively activated macrophages are associated with the activation of macrophages via the IL4R alpha. Despite a breadth of inflammatory pathologies associated with the large intestine, including those that accompany parasitic infection, it is not known how colonic macrophages are activated towards an alternatively activated phenotype. Here, we address this important knowledge gap by using Trichuris muris infection, in combination with transgenic mice (IL4R alpha fl/fl.CX3CR1Cre) and IL4R alpha-deficient/wild-type mixed bone marrow chimaeras. We make the unexpected finding that education of colonic macrophages towards a RELM alpha+, alternatively activated macrophage phenotype during T. muris infection does not require IL4R alpha expression on macrophages. Further, this independence is maintained even when the mice are treated with an anti-IFN gamma antibody during infection to create a strongly polarised Th2 environment. In contrast to RELM alpha, PD-L2 expression on macrophages post infection was dependent on IL4R alpha signalling in the macrophages. These novel data sets are important, revealing a surprising cell-intrinsic IL4R alpha independence of the colonic RELM alpha+ alternatively activated macrophage during Trichuris muris infection.

Automated summary

The study shows that colonic macrophages can express RELM alpha protein without responding to IL-4 and IL-13 during Trichuris muris infection. This finding is important for understanding and potentially treating inflammatory conditions.