P070 - MACROPHAGE-EXPRESSED ERBB4 PLAYS A PROTECTIVE ROLE IN THE ONSET AND RESOLUTION OF EXPERIMENTAL COLITIS
(Room Poster Hall)
19 Jan 18
5:30 PM
-
7:00 PM
Tracks:
Clinical and Research Challenges
Background: Pro-inflammatory macrophages (Mø) are crucial for onset of intestinal inflammation, and defects that enable persistence of these cells may contribute to inflammatory bowel disease. We recently showed that the ErbB4 receptor tyrosine kinase is induced on Mø by pro-inflammatory activation, and that subsequent stimulation with the ErbB4-specific ligand neuregulin-4 kills these cells. This suggests that Mø-expressed ErbB4 limits inflammation, but the cell type specificity of this effect and the role of ErbB4 in regulating colitis onset and recovery in vivo is untested. We hypothesize that selective Mø-expressed ErbB4 limits onset and promotes recovery from experimental colitis. Methods: To test the cell type specificity of ErbB4 induction, we generated bone-marrow derived Mø, dendritic cells, and neutrophils from C57BL/6 mice. To test the role of ErbB4 in experimental colitis, mice with a myeloid cell-specific ErbB4 deletion (LysMCre/ErbB4FF) were crossed with IL-10KO mice (LysMCre/ErbB4FF/IL-10KO) or subjected to a DSS colitis recovery model (6 days DSS + 6 days water). Results: The induction (ten-fold, p<0.01) of ErbB4 seen in pro-inflammatory Mø was not observed in activated dendritic cells or neutrophils. LysMCre/ErbB4FF/IL-10KO displayed inflammation markers (elevated fecal lipocalin-2 and colonic IL-17) by 8 weeks of age, when littermate controls were still healthy. LysMCre/ErbB4FF mice had impaired weight recovery, shorter colon lengths, and elevated fecal lipocalin-2 levels (p<0.05 versus littermate controls) 12 days after DSS. Summary/Conclusion: ErbB4 induction by challenge in innate immune cells was specific to pro-inflammatory Mø. Loss of Mø ErbB4 signaling accelerated IL-10KO colitis onset and impaired recovery from DSS colitis, suggesting that this receptor normally drives an anti-inflammatory feedback loop that limits colitis onset and promotes resolution.