NRG4-ErbB4 signaling represses proinflammatory macrophage activity

Macrophages are critical mediators of intestinal defense and homeostasis. However, uncontrolled proinflammatory macrophage activity may contribute to chronic conditions such as inflammatory bowel disease. Currently, the regulatory feedback mechanisms restraining proinflammatory cytokine production in activated macrophages are not well understood. The ErbB4 receptor tyrosine kinase is induced on macrophages by proinflammatory stimulation, and chronic ErbB4 activation with its ligand NRG4 drives macrophage apoptosis after 2 days. However, the impact of endogenous NRG4/ErbB4 signaling on macrophage function remains untested. Using bone marrow-derived ErbB4-null or NRG4-null macrophages, we tested the hypothesis that NRG4/ErbB4 signaling inhibits proinflammatory cytokine production. We found that deletion of either the receptor or its ligand resulted in elevated proinflammatory cytokine expression in classically (IFNγ/LPS) activated cells, compared with activated cells generated from wild-type littermates. NRG4 was induced by IFNγ/LPS activation in wild-type macrophages, and exogenous treatment with NRG4 led to a reduction in Tnf, Cxcl1, and Il1b expression within 24 h. RNA sequencing of ErbB4(myeKO) macrophages showed elevated expression of major regulators of inflammatory skewing (Sik2) and cytokine transport (Trim16). In vivo, ErbB4(myeKO) mice subjected to acute DSS colitis showed exaggerated disease, and ErbB4 myeloid knockout in the IL 10-KO chronic colitis model accelerated disease onset. Taken together, these findings demonstrate that NRG4/ErbB4 signaling in macrophages restrains the proinflammatory tone of these cells and is an important limiting regulator of colitis severity. These results highlight a previously unknown feedback mechanism by which growth factor signaling in immune cells prevents runaway inflammation and chronic disease. NEW & NOTEWORTHY Proinflammatory macrophages are essential drivers of colitis and express the growth factor receptor ErbB4. This study tested the role of ErbB4 and its specific ligand, NRG4, in regulating macrophage function. We show that endogenous NRG4-ErbB4 signaling limits macrophage production of proinflammatory cytokines in vitro and limits colitis severity in vivo and thus is a potential target for therapeutic intervention.