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* Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA 30322;
Department of General Surgery, University of Muenster, Muenster, Germany; and
The William Harvey Research Institute, Barts and The London School of Medicine, London, United Kingdom
During mucosal inflammation, a complex array of proinflammatory and protective mechanisms regulates inflammation and severity of injury. Secretion of anti-inflammatory mediators is a mechanism that is critical in controlling inflammatory responses and promoting epithelial restitution and barrier recovery. AnxA1 is a potent anti-inflammatory protein that has been implicated to play a critical immune regulatory role in models of inflammation. Although AnxA1 has been shown to be secreted in intestinal mucosal tissues during inflammation, its potential role in modulating the injury/inflammatory response is not understood. In this study, we demonstrate that AnxA1-deficient animals exhibit increased susceptibility to dextran sulfate sodium (DSS)-induced colitis with greater clinical morbidity and histopathologic mucosal injury. Furthermore, impaired recovery following withdrawal of DSS administration was observed in AnxA1 (–/–) animals compared with wild-type (WT) control mice that was independent of inflammatory cell infiltration. Since AnxA1 exerts its anti-inflammatory properties through stimulation of ALX/FPRL-1, we explored the role of this receptor-ligand interaction in regulating DSS-induced colitis. Interestingly, treatment with an ALX/FPRL-1 agonist, 15-epi-lipoxin A4 reversed the enhanced sensitivity of AnxA1 (–/–) mice to DSS colitis. In contrast, 15-epi-lipoxin A4 did not significantly improve the severity of disease in WT animals. Additionally, differential expression of ALX/FPLR-1 in control and DSS-treated WT and AnxA1-deficient animals suggested a potential role for AnxA1 in regulating ALX/FPRL-1 expression under pathophysiological conditions. Together, these results support a role of endogenous AnxA1 in the protective and reparative properties of the intestinal mucosal epithelium.
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1 This work was supported by grants from the National Institutes of Health (DK 59888 and DK 55679 to A.N.), (R01-DK72564 and R01-DK61379 to C.A.P.), (K08 DK074706-01 to B.A.B.), DK64399 (National Institutes of Health Digestive Disease Research Center tissue culture and morphology cores), and T32 DK007771 (C.T.C. and E.P.); Crohn’s and Colitis Foundation of America fellowship award (P.N.D.); and the German Research Foundation (Deutsche Forschungsgemeinschaft-La 2359/1-1 to M.G.L.).
2 B.A.B. and M.G.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Asma Nusrat, Department of Pathology and Laboratory Medicine, Emory University, Whitehead Biomedical Building #105M, 615 Michael Street, Atlanta, GA 30322. E-mail address: anusrat{at}emory.edu
4 Abbreviations used in this paper: FPR, formyl peptide receptor; DAI, disease activity index; DSS, dextran sulfate sodium; WT, wild type; MPO, myeloperoxidase.
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