Fc gamma receptor-TLR cross-talk elicits pro-inflammatory cytokine production by human M2 macrophages

Abstract

M2 macrophages suppress inflammation in numerous disorders, including tumour formation, infection and obesity. However, the exact role of M2 macrophages in the context of several other diseases is still largely undefined. We here show that human M2 macrophages promote inflammation instead of suppressing inflammation on simultaneous exposure to complexed IgG (c-IgG) and TLR ligands, as occurs in the context of diseases such as rheumatoid arthritis (RA). c-IgG-TLR ligand co-stimulation of M2 macrophages selectively amplifies production of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 and promotes Th17 responses, which all play a critical role in RA pathology. Induction of pro-inflammatory cytokines on c-IgG co-stimulation mainly depends on Fc gamma receptor IIa (FcγRIIa), which selectively amplifies cytokine gene transcription and induces caspase-1 activation. These data indicate that FcγR-TLR cross-talk may be targeted for treatment to attenuate inflammation in RA, by restoring the anti-inflammatory function of M2 macrophages.

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

“…This process causes a vicious cycle wherein each disease flare can initiate further autoantibody production and tissue injury (107)(108)(109). Furthermore, combined TLR-and Fc receptor-mediated activation of myeloid cells often leads to an enhanced inflammatory response that is thought to contribute to the chronicity of inflammation (51,94,110,111). Therefore, those self-antigens that can most potently activate B cells because they are TLR ligands may also potently enhance pathogenic inflammatory responses (Figure 3).…”

FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

“…A role for IL-1, IL-6, and LPS signal that utilizes MyD88 an adaptor for Toll/IL-1 receptor is implicated in overcoming the suppression by Tregs (55)(56)(57). Cooperation among Fc␥R-TLR signaling in M1 and M2 macrophages activates Syk kinase, which then produces proinflammatory cytokines (58). An association of TLR4 with Fc␥RIII upon ICs stimulation of mouse macrophages is observed (59).…”

Antibodies enhance CXCL10 production during RSV infection of infant and adult immune cells

“…Therefore, it is more likely that the phenomenon that we describe occurs on the membrane. A growing body of evidence shows that FccRII is able to cross-talk with multiple TLRs, IL-1R and IFNcR, thereby inducing enhanced cytokine profiles [39][40][41][42]. This is possibly also the mechanism behind our observations.…”