Journal
JOURNAL OF IMMUNOLOGY
Volume 195, Issue 8, Pages 3901-3911Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1500967
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Funding
- Flight Attendant Medical Research Institute Grant [103007]
- National Institutes of Health [AI109317-01A1, AI101973-01, AI097532-01A1]
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Earlier studies reported that a cell membrane protein, Annexin A2 (AnxA2), plays multiple roles in the development, invasion, and metastasis of cancer. Recent studies demonstrated that AnxA2 also functions in immunity against infection, but the underlying mechanism remains largely elusive. Using a mouse infection model, we reveal a crucial role for AnxA2 in host defense against Pseudomonas aeruginosa, as anxa2(-/-) mice manifested severe lung injury, systemic dissemination, and increased mortality compared with wild-type littermates. In addition, anxa2(-/-) mice exhibited elevated inflammatory cytokines (TNF-alpha, IL-6, IL-1 beta, and IFN-gamma), decreased bacterial clearance by macrophages, and increased superoxide release in the lung. We further identified an unexpected molecular interaction between AnxA2 and Fam13A, which activated Rho GTPase. P. aeruginosa infection induced autophagosome formation by inhibiting Akt1 and mTOR. Our results indicate that AnxA2 regulates autophagy, thereby contributing to host immunity against bacteria through the Akt1-mTOR-ULK1/2 signaling pathway.
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