Abstract

Background and objective While pro-inflammatory monocyte trafficking to the intestine has been partially characterised, the molecules required for migration of tolerogenic mononuclear phagocytes (dendritic cells (DC) and macrophages) are unknown. We hypothesised that the gut-homing receptor integrin alpha 4 beta 7 is required for this process. Methods We used a T cell-mediated colitis model to study the role of alpha 4 beta 7 in the innate immune compartment. We then performed competitive bone marrow (BM) reconstitution experiments to assess the requirement of alpha 4 beta 7 in the generation of intestinal retinoic acid (RA)-producing CD11c(hi) DC (ALDE(+)DC) and CD64 macrophages. Using mixed BM chimeras we also asked whether alpha 4 beta 7 is required to give rise to tolerogenic mononuclear phagocytes. Results Lack of beta 7 integrins in the innate immune compartment (beta 7(-/-)RAG2(-/-) mice) markedly accelerated T cell-mediated colitis, which was correlated with lower numbers and frequencies of ALDE(+)DC in mesenteric lymph nodes. Consistent with a role of alpha 4 beta 7 in the generation of intestinal mononuclear phagocytes, BM cells from beta 7(-/-) mice poorly reconstituted small intestine ALDE(+)DC and M. when compared to their wild type counterparts. In addition, mice lacking beta 7 integrins in the CD11c(hi) compartment showed decreased ability to induce Foxp3(+) T-REG and IL-10-producing T cells. Conclusions Mice lacking beta 7 integrins in the innate immune compartment are more susceptible to intestinal inflammation, which is correlated with a requirement of beta 7 integrins to reconstitute gut mononuclear phagocytes with tolerogenic potential.