Abstract
Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance1,2. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors3. Here we show that the FcRγ adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRγâ/â mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-α. The FcRγ-associated receptor that inhibits E. coli phagocytosis is FcγRIII (also called CD16), and its absence protects mice from sepsis. FcγRIII binds E. coli, and this interaction induces FcRγ phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-α production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRγ on macrophages as the class A scavenger receptor MARCO. E. coli-FcγRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcγRIII, E. coli triggers an inhibitory FcRγ pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-α secretion.
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Acknowledgements
We thank J. Ravetch (Rockefeller University, New York) for kindly providing the FcRγâ/â mice, A. Veillette (Clinical Research Institute of Montreal, Montréal, Canada) for the antibody to SHIP, G. Kraal (VU University Medical Center, Amsterdam, Netherlands) for the mAb to MARCO and Y. Kanamaru for technical advice. F.P.d.S. was supported by CNPq, the Brazilian National Council for Scientific Development, Ministry of Science and Technology (grant 200739). M.C. is supported by the State of São Paulo Research Foundation (FAPESP) (grant 03/14148-8). R.C.M. was supported by the French National Institute for Health and Medical Research (INSERM) and the Agence Nationale pour la Recherche (ANR âMIMEâ) 2006.
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F.P.d.S. performed the main experiments and data analysis for phagocytosis and mouse survival. M.A. performed the main experiments for signaling analysis. D.S. performed experiments for microbiological analysis. M.B., A.A., I.T.V. and M.C. were involved in data analysis and/or writing. J.S.V. generated FcγRIIIâ/â mice. P.L. planned and performed experiments for gene silencing. R.C.M. was responsible for project planning, data analysis, discussion and writing.
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Pinheiro da Silva, F., Aloulou, M., Skurnik, D. et al. CD16 promotes Escherichia coli sepsis through an FcRγ inhibitory pathway that prevents phagocytosis and facilitates inflammation. Nat Med 13, 1368â1374 (2007). https://doi.org/10.1038/nm1665
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DOI: https://doi.org/10.1038/nm1665
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