Annexin A1 regulates intestinal mucosal injury, inflammation, and repair

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.
Babbin, Brian A Laukoetter, Mike G Nava, Porfirio Koch, Stefan Lee, Winston Y Capaldo, Christopher T Peatman, Eric Severson, Eric A Flower, Roderick J Perretti, Mauro Parkos, Charles A Nusrat, Asma eng K08 DK074706/DK/NIDDK NIH HHS/ R01 DK059888-09/DK/NIDDK NIH HHS/ R01 DK061379-08/DK/NIDDK NIH HHS/ R29 DK055679/DK/NIDDK NIH HHS/ T32 GM008169/GM/NIGMS NIH HHS/ K08 DK074706-02/DK/NIDDK NIH HHS/ R01-DK61379/DK/NIDDK NIH HHS/ DK 55679/DK/NIDDK NIH HHS/ DK64399/DK/NIDDK NIH HHS/ R01 DK072564/DK/NIDDK NIH HHS/ T32 DK007771-09/DK/NIDDK NIH HHS/ R24 DK064399/DK/NIDDK NIH HHS/ R01 DK055679-11A1/DK/NIDDK NIH HHS/ R24 DK064399-019003/DK/NIDDK NIH HHS/ R01 DK055679/DK/NIDDK NIH HHS/ DK 59888/DK/NIDDK NIH HHS/ R01 DK061379/DK/NIDDK NIH HHS/ R01-DK72564/DK/NIDDK NIH HHS/ T32 DK007771/DK/NIDDK NIH HHS/ R01 DK059888/DK/NIDDK NIH HHS/ K08 DK074706-01/DK/NIDDK NIH HHS/ R01 DK072564-15/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2008/09/20 09:00 J Immunol. 2008 Oct 1;181(7):5035-44.