CD16 promotes Escherichia coli sepsis through an FcRγ inhibitory pathway that prevents phagocytosis and facilitates inflammation

Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance(1,2). Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors(3). Here we show that the FcR gamma adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcR gamma(-/-) 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)-alpha. The FcR gamma-associated receptor that inhibits E. coli phagocytosis is Fc gamma RIII (also called CD16), and its absence protects mice from sepsis. Fc gamma RIII binds E. coli, and this interaction induces FcR gamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-alpha production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcR gamma on macrophages as the class A scavenger receptor MARCO. E. coli-Fc gamma RIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FccRIII, E. coli triggers an inhibitory FcR gamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-a secretion.