Reversal of Proinflammatory Responses by Ligating the Macrophage Fcγ Receptor Type I

Abstract

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 Fcγ receptors (FcγR) 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 FcγR ligation, since the ligation of the Mac-1 receptor did not alter IL-10 production. The identification of the specific FcγR subtype responsible for IL-10 upregulation was determined in gene knockout mice. Macrophages from mice lacking the FcR γ chain, which is required for assembly and signaling by FcγRI and FcγRIII, failed to upregulate IL-10 in response to immune complexes. However, mice lacking either the FcγRII or the FcγRIII were fully capable of upregulating IL-10 production, implicating FcγRI in this process. The biological consequences of FcγRI ligation were determined in both in vitro and in vivo models of inflammation and sepsis. In all of the models tested, the ligation of FcγR 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 FcγR-mediated clearance in suppressing macrophage proinflammatory responses.

Lipopolysaccharide Induces Rapid Production of IL-10 by Monocytes in the Presence of Apoptotic Neutrophils

“…IL-10 production was increased from 342 Ϯ 10 to 696 Ϯ 203 pg/ml in the presence of apoptotic neutrophils and further increased to 1101 Ϯ 203 pg/ml in the presence of opsonized neutrophils (Table II). This up-regulation of IL-10 by opsonized cells is consistent with published data (22,31). These data collectively demonstrate that the induction of reduced proinflammatory cytokine production by monocytes coupled with the promotion of augmented IL-10 production are specific to apoptotic neutrophils.…”

“…Similarly, in the presence of opsonized apoptotic neutrophils, which would trigger the CD16 receptor, we show that LPS stimulation drives a proinflammatory response. This is a previously reported phenomenon of CD16 ligation (22,31). This is the first report to define the interaction between apoptotic neutrophils and blood monocytes.…”

Suppression of IL-12 Transcription in Macrophages Following Fcγ Receptor Ligation

“…Densitometric quantitation of three separate RNase protection assays indicated that whereas IL-12 mRNA levels decreased by Ͼ90%, the mRNA levels for MIF, IL-6, and IL-1RA were not significantly diminished following Fc␥R ligation. A single other gene, IL-10, was increased following Fc␥R ligation, as previously reported (37). The addition of control unopsonized erythrocytes, which do not bind to specific macrophage receptors, did not affect cytokine mRNA production.…”

“…LPS from Escherichia coli 0127:B8 was purchased from Sigma (St. Louis, MO). IgG-opsonized erythrocytes (EIgG) were generated by incubating sheep erythrocytes (Lampire, Pipersville, PA) with rabbit anti-sheep erythrocyte IgG (Cappel, Durham, NC) at nonagglutinating titers for 40 min at room temperature, as previously described (37). EIgG were washed with HBSS (Life Technologies, Grand Island, NY) and resuspended at 2 ϫ 10 8 cells/ml and used the same day.…”

Up-regulation of Gr1+CD11b+ cell population in the spleen of NaClO-administered mice works to repair skin wounds

“…'Regulatory' macrophages can secrete large amounts of interleukin-10 (IL-10) in response to Fc receptor-γ ligation [11,12]. In contrast to pro-inflammatory and anti-microbial M1 macrophage responses, M2 macrophages exhibit potent anti-inflammatory activity and have important roles in wound healing and fibrosis [13,14].…”