This week on TIBDI! Neutrophils shed a protein that disrupts the intestinal barrier, hormones and T cells are behind Crohn’s disease gender skewing, and CD31 is the newest way to make dendritic cells anti-inflammatory.
Neutrophils Bust Up the Intestinal Barrier
During inflammatory bowel disease (IBD), neutrophils gather at sites of inflammation and often migrate through the intestinal epithelial barrier. A new model described by Dr. Dominique A. Weber and Dr. Ronen Sumagin now shows how dangerous this behavior is for intestinal wound healing. They found that neutrophils shed junctional adhesion molecule-like protein (JAML) during epithelial transmigration. JAML binds to a receptor found on epithelial cells called coxsackie-adenovirus receptor (CAR), and JAML and CAR interactions cause epithelial barriers to become leaky. While this leakiness may be needed for initial efficient immune cell infiltration, shed JAML prevents the barrier from regaining normal function and stops wound closure. Experiments showed that blocking JAML-CAR interactions could lead to accelerated wound repair. This discovery could help treat IBD-induced intestinal ulcerations.
Why Crohn’s Disease Prefers Women
There is a general acceptance that the prevalence of Crohn’s disease (CD) is higher in women than in men. W.A. Goodman and R.R. Garg of Case Western Reserve University School of Medicine suspected that this gender bias might be the same in spontaneous models of CD. This is, indeed, the situation. Female SAMP1/YitFc (SAMP) mice were more predisposed to spontaneous CD and had impaired regulatory T cells with low frequencies as compared to the male SAMP mice. An investigation of the T cells revealed that male SAMP T cells responded much differently than female SAMP T cells to estrogen signals. While the male T cells responded by increasing immunosuppressive functions and expanding regulatory T cells, the female cells were resistant to these signals. Finding ways to make female T cells sensitive to estrogen signals could decrease female susceptibility to CD.
More Ways to Induce Anti-inflammatory Dendritic Cells
CD31 is expressed on many types of immune cells and endothelial cells, and it is mainly seen as an adhesion and migration molecule. Recent evidence has shown that it also has inhibitory function on T cells, which means that it might have inhibitory functions in other cells. Marc Clement of the French National Institute of Health and Medical Research (INSERM) has now found that this is, indeed, the situation with dendritic cells (DCs). Signaling via CD31 prevented DC maturation, migration and reduced pro-inflammatory signaling cascades. CD31-stimulated DC also preferentially polarized T cells towards a regulatory phenotype, and transfer of these DCs to a rodent model of multiple sclerosis delayed disease development. These results suggest that CD31 may also be potentially interesting for IBD.
- Clement, M., Fornasa, G., Guedj, K., Ben Mkaddem, S., Gaston, A. T., Khallou-Laschet, J., et al. (2014). CD31 is a key coinhibitory receptor in the development of immunogenic dendritic cells. Proceedings of the National Academy of Sciences of the United States of America. doi:10.1073/pnas.1314505111
- Goodman, W. A., Garg, R. R., Reuter, B. K., Mattioli, B., Rissman, E. F., & Pizarro, T. T. (2014). Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn’s-like ileitis. Mucosal Immunology. 1–11. doi:10.1038/mi.2014.15
- Weber, D. A., Sumagin, R., McCall, I. C., Leoni, G., Neumann, P. A., Andargachew, R., et al. (2014). Neutrophil-derived JAML inhibits repair of intestinalepithelial injury during acute inflammation. Mucosal Immunology. 1–12. doi:10.1038/mi.2014.12