Reversal of proinflammatory responses by ligating the macrophage Fcγ receptor type I

Macrophages can respond to a variety of infectious and/or inflammatory stimuli by secreting an array of proinflammatory cytokines, the overproduction of which can result in shock or even death. In this report, we demonstrate that ligation of macrophage Fc gamma receptors (Fc gamma R) can lead to a reversal of macrophage proinflammatory responses by inducing an upregulation of interleukin (IL)-10, with a reciprocal inhibition of IL-12 production. IL-10 upregulation was specific to Fc gamma R ligation, since the ligation of the Mac-1 receptor did not alter IL-10 production. The identification of the specific Fc gamma R subtype responsible for IL-10 upregulation was determined in gene knockout mice. Macrophages from mice lacking the FcR gamma chain, which is required for assembly and signaling by Fc gamma RI and Fc gamma RIII, failed to upregulate IL-10 in response to immune complexes. However, mice lacking either the Fc gamma RII or the Fc gamma RIII were fully capable of upregulating IL-10 production, implicating Fc gamma RI in this process. The biological consequences of Fc gamma RI ligation were determined in both in vitro and in vivo models of inflammation and sepsis. In all of the models tested, the ligation of Fc gamma R promoted the production of IL-10 and inhibited the secretion of IL-12. This reciprocal alteration in the pattern of macrophage cytokine production illustrates a potentially important role for Fc gamma R-mediated clearance in suppressing macrophage proinflammatory responses.