A mutation that blocks integrin α4β7 activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis
Hailong Zhang,
Yajuan Zheng,
Youdong Pan,
Changdong Lin,
Shihui Wang,
Zhanjun Yan,
Ling Lu,
Gaoxiang Ge,
Jinsong Li,
Yi Arial Zeng,
Jianfeng Chen
Affiliations
Hailong Zhang
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Yajuan Zheng
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Youdong Pan
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Changdong Lin
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Shihui Wang
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Zhanjun Yan
Department of Orthopedics, the First People’s Hospital of Wujiang District
Ling Lu
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Gaoxiang Ge
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Jinsong Li
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Yi Arial Zeng
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Jianfeng Chen
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences
Abstract Background 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 gut epithelial cells by interacting with E-cadherin. Integrin β7 blocking antibodies have shown efficacy in clinical management of inflammatory bowel disease (IBD); however, fully blocking β7 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 β7 is required to avoid this adverse effect. Results Herein, we inhibited integrin α4β7 activation in vivo by creating mice that carry in their integrin β7 gene a mutation (F185A) which from structural studies is known to lock α4β7 in its resting state. Lymphocytes from β7-F185A knock-in (KI) mice expressed α4β7 integrins that could not be activated by chemokines and showed significantly impaired homing to the gut. The β7-F185A mutation did not inhibit αEβ7 activation, but led to the depletion of αEβ7 + lymphocytes in the spleen and a significantly reduced population of αEβ7 + lymphocytes in the gut of KI mice. β7-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 β7 function. Conclusions Our findings demonstrate that specific inhibition of integrin α4β7 activation is a potentially better strategy than fully blocking α4β7 function for IBD treatment.
