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The Matricellular Protein CCN1 Regulates Colitis, Colitis-Associated Cancer, And Neutrophil Mobilization

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posted on 01.07.2016, 00:00 authored by Jacob S. Choi
The matricellular protein CCN1 (CYR61) is known to function in inflammation, wound healing and tissue repair, and its expression is increased in colons of patients with Crohn’s disease and ulcerative colitis. Here we have sought to determine the role of CCN1 in colonic inflammation, mucosal repair, and colitis-associated tumorigenesis. In addition, we investigated the involvement of CCN1 in coordinating systemic inflammatory response. We have used two knockin mice, Ccn1dm/dm and Ccn1d125a/d125a, expressing a CCN1 mutant unable to bind integrins α6β1 and αMβ2, and αVβ3, respectively, as a model to probe CCN1 functions in dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)-DSS carcinogenesis. Ccn1dm/dm and Ccn1d125a/d125a mice exhibited high mortality in DSS-induced colitis; however, the respective defects contributing to the disease process were different in the mutant animals. Ccn1d125a/d125a mice were highly susceptible to severe, acute inflammation and exhibited propensity to develop chronic inflammation after DSS challenge. Further examination revealed that Ccn1d125a/d125a mutation altered the integrity of the intestinal mucosal barrier to trigger uncontrolled inflammation and greater tissue injury. In contrast, Ccn1dm/dm mice showed impaired mucosal healing and a deficit in IL-6 expression during the repair phase of DSS-induced colitis compared to wild type mice, despite having comparable severity of initial inflammation and tissue injury. CCN1-induced IL-6 expression in macrophages through integrin αMβ2 and in fibroblasts through α6β1, and IL-6 promotes intestinal epithelial cell (IEC) proliferation. Administration of purified CCN1 protein fully rescued Ccn1dm/dm mice from DSS-induced mortality, restored IEC proliferation and enhanced mucosal healing, whereas delivery of IL-6 partially rectified these defects. CCN1 therapy accelerated mucosal healing and recovery from disease symptoms after DSS-induced colitis even in wild type mice. These findings suggest a therapeutic potential for targeting activating the CCN1/IL-6 axis for inflammatory bowel disease. CCN1 also suppressed colitis-associated tumorigenesis. Lastly, we found that exogenous CCN1 can induce neutrophilia in a dose-dependent manner by regulating expression of granulocyte-colony stimulating factor (G-CSF). Taken collectively, CCN1 is a critical modulator of local and systemic inflammation with important functions in tissue repair and inflammation-associated tumorigenesis.

History

Advisor

Lau, Lester

Department

Biochemistry and Molecular Genetics

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Ackerman, Steven J. Merrill, Brad Tyner, Angela Xu, Jingsong

Submitted date

2016-05

Language

en

Issue date

01/07/2016