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Antibody secreting cells are critically dependent on integrin α4β7/MAdCAM-1 for intestinal recruitment and control of the microbiota during chronic colitis.

ABSTRACT: T and B cells employ integrin α4β7 to migrate to intestine under homeostatic conditions. Whether those cells differentially rely on α4β7 for homing during inflammatory conditions has not been fully examined. This may have implications for our understanding of the mode of action of anti-integrin therapies in inflammatory bowel disease (IBD). Here, we examined the role of α4β7 integrin during chronic colitis using IL-10^-/- mice, β7-deficient IL-10^-/-, IgA-deficient IL-10^-/- mice, and antibody blockade of MAdCAM-1. We found that α4β7 was predominantly expressed by B cells. β7 deficiency and MAdCAM-1 blockade specifically depleted antibody secreting cells (ASC) (not T cells) from the colonic LP, leading to a fecal pan-immunoglobulin deficit, severe colitis, and alterations of microbiota composition. Colitis was not due to defective regulation, as dendritic cells (DC), regulatory T cells, retinaldehyde dehydrogenase (RALDH) expression, activity, and regulatory T/B-cell cytokines were all comparable between the strains/treatment. Finally, an IgA deficit closely recapitulated the clinical phenotype and altered microbiota composition of β7-deficient IL-10^-/- mice. Thus, a luminal IgA deficit contributes to accelerated colitis in the β7-deficient state. Given the critical/nonredundant dependence of IgA ASC on α4β7:MAdCAM-1 for intestinal homing, B cells may represent unappreciated targets of anti-integrin therapies.

SUBMITTER: Tyler CJ

PROVIDER: S-EPMC8732264 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsAberrant lymphocyte homing could potentially link inflammatory processes in the intestine and the liver, as distinct hepatobiliary diseases frequently develop as extra-intestinal manifestations in inflammatory bowel disease. In this study, we examined the role of the gut-tropic leukocyte adhesion molecule β7 integrin and its endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) in immune-mediated hepatitis in mice.MethodsWild-type (WT) mice, MAdCAM-1-deficient mice, β7 integrin-deficient mice, RAG-2-deficient mice, RAG-2/MAdCAM-1 double-deficient mice, and RAG-2/β7 integrin double-deficient mice were subjected to concanavalin A (ConA)-induced hepatitis. The degree of hepatitis was evaluated by histology, flow cytometry, and expression analysis of inflammatory mediators. The motility of lymphocytes in progressive liver damage was assessed by intravital laser scanning multiphoton microscopy.ResultsAblation of MAdCAM-1 or β7 integrin ameliorated ConA-induced hepatitis in mice. β7 integrin-deficient lymphocytes caused less liver damage than WT lymphocytes in ConA-treated RAG-2-deficient mice. Moreover, WT lymphocytes caused less liver damage in ConA-treated RAG-2/β7 integrin double-deficient mice than in similarly treated RAG-2-deficient mice, indicating that β7 integrin expression contributes significantly to the liver damage mediated by innate immune cells. MAdCAM-1 expression was dependent on β7 integrin expression on adaptive and innate immune cells. Most importantly, lymphocytes in ConA-treated MAdCAM-1-deficient mice displayed more motility and less adhesion in the liver sinusoids in vivo, than lymphocytes in similarly treated WT mice.ConclusionsThese data suggest that β7 integrin expression on lymphocytes and innate immune cells contributes to MAdCAM-1 upregulation and liver damage in acute immune-mediated hepatitis, most likely by facilitating lymphocyte/sinusoidal endothelial cell interactions.

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Antibody secreting cells are critically dependent on integrin α4β7/MAdCAM-1 for intestinal recruitment and control of the microbiota during chronic colitis.

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