Dataset Information

A mutation that blocks integrin ?₄?₇ activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis.

ABSTRACT:

Background

?₇ integrins are responsible for the efficient recruitment of lymphocytes from the blood and their retention in gut-associated lymphoid tissues. Integrin ?₄?₇ binds MAdCAM-1, mediating rolling adhesion of lymphocytes on blood vessel walls when inactive and firm adhesion when activated, thereby controlling two critical steps of lymphocyte homing to the gut. By contrast, integrin ?_E?₇ mediates the adhesion of lymphocytes to gut epithelial cells by interacting with E-cadherin. Integrin ?₇ blocking antibodies have shown efficacy in clinical management of inflammatory bowel disease (IBD); however, fully blocking ?₇ function leads to the depletion of colonic regulatory T (Treg) cells and exacerbates dextran sulfate sodium (DSS)-induced colitis by evoking aberrant innate immunity, implying its potential adverse effect for IBD management. Thus, a better therapeutic strategy targeting integrin ?₇ is required to avoid this adverse effect.

Results

Herein, we inhibited integrin ?₄?₇ activation in vivo by creating mice that carry in their integrin ?₇ gene a mutation (F185A) which from structural studies is known to lock ?₄?₇ in its resting state. Lymphocytes from ?₇-F185A knock-in (KI) mice expressed ?₄?₇ integrins that could not be activated by chemokines and showed significantly impaired homing to the gut. The ?₇-F185A mutation did not inhibit ?_E?₇ activation, but led to the depletion of ?_E?₇⁺ lymphocytes in the spleen and a significantly reduced population of ?_E?₇⁺ lymphocytes in the gut of KI mice. ?₇-F185A KI mice were resistant to T cell transfer-induced chronic colitis, but did not show an increased susceptibility to DSS-induced innate colitis, the adverse effect of fully blocking ?₇ function.

Conclusions

Our findings demonstrate that specific inhibition of integrin ?₄?₇ activation is a potentially better strategy than fully blocking ?₄?₇ function for IBD treatment.

SUBMITTER: Zhang H

PROVIDER: S-EPMC7288534 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A mutation that blocks integrin α4β7 activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis.

Zhang Hailong H Zheng Yajuan Y Pan Youdong Y Lin Changdong C Wang Shihui S Yan Zhanjun Z Lu Ling L Ge Gaoxiang G Li Jinsong J Zeng Yi Arial YA Chen Jianfeng J

BMC biology 20200610 1

<h4>Background</h4>β7 integrins are responsible for the efficient recruitment of lymphocytes from the blood and their retention in gut-associated lymphoid tissues. Integrin α4β7 binds MAdCAM-1, mediating rolling adhesion of lymphocytes on blood vessel walls when inactive and firm adhesion when activated, thereby controlling two critical steps of lymphocyte homing to the gut. By contrast, integrin αEβ7 mediates the adhesion of lymphocytes to ...[more]

PMID: 32522281

Similar Datasets

Project description:UnlabelledBackgroundInterleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R) are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer.MethodsWe examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb)-induced colitis in immune-sufficient Mdr1a-/- mice and in T- and B-cell-deficient Rag2-/- mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression.ResultsTreatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a-/- mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a-/- mice treated with an anti-IL-7R antibody. In Rag2-/- mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity.ConclusionsResults from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development in Hb-infected mice by controlling the expansion of multiple leukocyte populations, as well as the activity of these immune cells. Our findings demonstrate an important function of IL-7R-driven immunity in experimental colitis and indicate that the therapeutic efficacy of IL-7R blockade involves affecting both adaptive and innate immunity.

Project description:Background: Ulcerative colitis (UC) is a chronic inflammatory gastrointestinal disease, notoriously challenging to treat. Previous studies have found a positive correlation between thymic atrophy and colitis severity. It was, therefore, worthwhile to investigate the effect of thymopentin (TP5), a synthetic pentapeptide corresponding to the active domain of the thymopoietin, on colitis. Methods: Dextran sulfate sodium (DSS)-induced colitis mice were treated with TP5 by subcutaneous injection. Body weight, colon length, colon weight, immune organ index, disease activity index (DAI) score, and the peripheral blood profile were examined. The immune cells of the spleen and colon were analyzed by flow cytometry. Histology was performed on isolated colon tissues for cytokine analysis. Bacterial DNA was extracted from mouse colonic feces to assess the intestinal microbiota. Intestinal lamina propria mononuclear cells (LPMCs), HCT116, CT26, and splenocytes were cultured and treated with TP5. Results: TP5 treatment increased the body weight and colon length, decreased the DAI score, and restored colon architecture of colitic mice. TP5 also decreased the infiltration of immune cells and expression levels of pro-inflammatory cytokines such as IL-6. Importantly, the damaged thymus and compromised lymphocytes in peripheral blood were significantly restored by TP5. Also, the production of IL-22, both in innate and adaptive lymphoid cells, was triggered by TP5. Given the critical role of IL-22 in mucosal host defense, we tested the effect of TP5 on mucus barrier and gut microbiota and found that the number of goblet cells and the level of Mucin-2 expression were restored, and the composition of the gut microbiome was normalized after TP5 treatment. The critical role of IL-22 in the protective effect of TP5 on colitis was further confirmed by administering the anti-IL-22 antibody (?IL-22), which completely abolished the effect of TP5. Furthermore, TP5 significantly increased the expression level of retinoic acid receptor-related orphan receptor ? (ROR?t), a transcription factor for IL-22. Consistent with this, ROR?t inhibitor abrogated the upregulation of IL-22 induced by TP5. Conclusion: TP5 exerts a protective effect on DSS-induced colitis by triggering the production of IL-22 in both innate and adaptive lymphocytes. This study delineates TP5 as an immunomodulator that may be a potential drug for the treatment of UC.

Dataset Information

A mutation that blocks integrin ?₄?₇ activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis.

Background

Results

Conclusions

Publications

A mutation that blocks integrin α<sub>4</sub>β<sub>7</sub> activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Dataset Information

A mutation that blocks integrin ?4?7 activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis.

Background

Results

Conclusions

Publications

A mutation that blocks integrin α<sub>4</sub>β<sub>7</sub> activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

A mutation that blocks integrin ?₄?₇ activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis.