Macrophage‐Specific ErbB4 is Induced by DSS Colitis and Regulates Macrophage Survival

Abstract

The ErbB4 receptor tyrosine kinase is induced in the colonic epithelium in inflammatory bowel disease (IBD), and the ErbB4-specific ligand neuregulin-4 is protective in murine colitis models. Interestingly, ErbB4 is also robustly detectable in the submucosal stroma where immune cells accumulate during inflammation. Previous studies have shown ErbB4 expression on circulating human monocytes and neuronal macrophages (Mø), but its expression on intestinal Mø and role in Mø biology are unknown. HYPOTHESIS: As Mø play a significant role in the development of acute colitis, we hypothesized that receptor-mediated ErbB4 signaling may be an anti-inflammatory mechanism to limit Mø numbers during inflammation. METHODS: Mice (C57Bl6) were given 3% dextran sodium sulfate (DSS) in drinking water for 4 days (injury phase) followed by 3 days without DSS (recovery phase); colonic Mø populations were characterized by flow cytometry. Murine bone marrow-derived Mø (BM-Mø) were generated for in vitro activation and survival studies. RESULTS: DSS induced colonic recruitment of F480+/CD11b+/Ly6C+/ErbB4+ cells in injury and recovery phase mice compared to controls. In vitro, classical activation (IFNγ/LPS) of BM-Mø, but not alternative activation (IL-4), induced ErbB4 expression 10-fold (*p<0.01). Treatment of these cells with neuregulin-4 (100 ng/ml) reduced activated BM-Mø numbers by 40% (*p<0.05) after 48 hours, an effect blocked by ErbB4 neutralizing antibody (2 μg/ml). CONCLUSION Colitis induces recruitment of ErbB4+ Mø. ErbB4 signaling is a possible inhibitory feedback mechanism restricting Mø numbers, and thus represents a potential therapeutic target to regulate inflammation in IBD.