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

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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

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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 Deep vein thrombosis (DVT) is the primary cause of pulmonary embolism and the third most life-threatening cardiovascular disease in North America. Post-DVT anticoagulants, such as warfarin, heparin, and direct oral anticoagulants, reduce the incidence of subsequent venous thrombi. However, all currently used anticoagulants affect bleeding time at various degrees, and there is therefore a need for improved therapeutic regimens in DVT. It has recently been shown that mast cells play a crucial role in a DVT murine model. The underlying mechanism involved in the prothrombotic properties of mast cells, however, has yet to be identified. Methods and Results C57BL/6 mice and mouse mast cell protease-4 (mMCP-4) genetically depleted mice (mMCP-4 knockout) were used in 2 mouse models of DVT, partial ligation (stenosis) and ferric chloride-endothelial injury model of the inferior vena cava. Thrombus formation and impact of genetically repressed or pharmacologically (specific inhibitor TY-51469) inhibited mMCP-4 were evaluated by morphometric measurements of thrombi immunochemistry (mouse and human DVT), color Doppler ultrasound, bleeding times, and enzymatic activity assays ex vivo. Recombinant chymases, mMCP-4 (mouse) and CMA-1 (human), were used to characterize the interaction with murine and human plasmin, respectively, by mass spectrometry and enzymatic activity assays. Inhibiting mast cell-generated mMCP-4, genetically or pharmacologically, resolves and prevents venous thrombus formation in both DVT models. Inferior vena cava blood flow obstruction was observed in the stenosis model after 6 hours of ligation, in control- but not in TY-51469-treated mice. In addition, chymase inhibition had no impact on bleeding times of healthy or DVT mice. Furthermore, endogenous chymase limits plasmin activity in thrombi ex vivo. Recombinant mouse or human chymase degrades/inactivates purified plasmin in vitro. Finally, mast cell-containing immunoreactive chymase was identified in human DVT. Conclusions This study identified a major role for mMCP-4, a granule-localized protease of chymase type, in DVT formation. These findings support a novel pharmacological strategy to resolve or prevent DVT without affecting the coagulation cascade through the inhibition of chymase activity.

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

Tweets

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

Tweets

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