Letter abstract
Nature Medicine 13, 1368 - 1374 (2007)
Published online: 14 October 2007 | doi:10.1038/nm1665
CD16 promotes Escherichia coli sepsis through an FcR
inhibitory pathway that prevents phagocytosis and facilitates inflammation
Fabiano Pinheiro da Silva1,2,3,8, Meryem Aloulou1,2,8, David Skurnik4, Marc Benhamou1,2, Antoine Andremont4, Irineu T Velasco3, Murilo Chiamolera3,5, J Sjef Verbeek6, Pierre Launay1,2,7 & Renato C Monteiro1,2
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 FcR
adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcR
-/- 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)-
. The FcR-associated receptor that inhibits E. coli phagocytosis is FcRIII (also called CD16), and its absence protects mice from sepsis. FcRIII binds E. coli, and this interaction induces FcR phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF- production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcR on macrophages as the class A scavenger receptor MARCO. E. coli-FcRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcRIII, E. coli triggers an inhibitory FcR pathway that both impairs MARCO-mediated bacterial clearance and activates TNF- secretion.
- Institut National de la Santé et de la Recherche Médicale U699, 16 rue Henri Huchard, Paris F-75018, France.
- University of Paris 7, Bichat Medical School, 16 rue Henri Huchard, Paris F-75018, France.
- Emergency Medicine Department, University of São Paulo, Av Dr Arnaldo 455, São Paulo 01246-903, Brazil.
- Bacteriology Department, Bichat-Claude Bernard Hospital and EA 6934 University of Paris 7, 46, rue Henri Huchard, Paris F-75018, France.
- Division of Rheumatology, University of São Paulo, Av Dr Arnaldo 455, São Paulo 01246-903, Brazil.
- Department of Human Genetics, Leiden University Medical Center, Postzone S4-P PO Box 9600, 2300 RC, Leiden, the Netherlands.
- Equipe Avenir Institut National de la Santé et de la Recherche Médicale, 16 rue Henri Huchard, Paris F-75018, France.
- These authors contributed equally to this work.
Correspondence to: Renato C Monteiro1,2 e-mail: monteiro@bichat.inserm.fr
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