Cross-Talk between TLR4 and FcγReceptorIII (CD16) Pathways

Abstract

Pathogen-pattern-recognition by Toll-like receptors (TLRs) and pathogen clearance after immune complex formation via engagement with Fc receptors (FcRs) represent central mechanisms that trigger the immune and inflammatory responses. In the present study, a linkage between TLR4 and FcγR was evaluated in vitro and in vivo. Most strikingly, in vitro activation of phagocytes by IgG immune complexes (IgGIC) resulted in an association of TLR4 with FcγRIII (CD16) based on co-immunoprecipitation analyses. Neutrophils and macrophages from TLR4 mutant (mut) mice were unresponsive to either lipopolysaccharide (LPS) or IgGIC in vitro, as determined by cytokine production. This phenomenon was accompanied by the inability to phosphorylate tyrosine residues within immunoreceptor tyrosine-based activation motifs (ITAMs) of the FcRγ-subunit. To transfer these findings in vivo, two different models of acute lung injury (ALI) induced by intratracheal administration of either LPS or IgGIC were employed. As expected, LPS-induced ALI was abolished in TLR4 mut and TLR4^−/− mice. Unexpectedly, TLR4 mut and TLR4^−/− mice were also resistant to development of ALI following IgGIC deposition in the lungs. In conclusion, our findings suggest that TLR4 and FcγRIII pathways are structurally and functionally connected at the receptor level and that TLR4 is indispensable for FcγRIII signaling via FcRγ-subunit activation. The immune system is traditionally divided into innate and adaptive entities. Pattern-recognition receptors (PRRs) collectively recognize molecular structures of invading microorganisms, followed by initiation of immune responses. PRRs comprise the toll-like receptor (TLR) family, including TLR4, which is essential for responses to bacterial lipopolysaccharide (LPS). As part of the adaptive immune system, Fc receptors (FcRs) on immune cells recognize antigen–antibody complexes and link antibody-mediated immune responses to cellular effector functions. Here, we describe cross-talk between the pathogen-recognition-receptor toll-like receptor 4 (TLR4) and receptors for IgG immune complexes (IgGIC), Fcγ receptors (FcγRs). We found that TLR4 is involved in FcγRIII (CD16) signaling and that heterodimerization of TLR4 and FcγRIII occurs in the presence of IgGIC but not LPS. Consequently, dysfunctional TLR4 signaling results in unresponsiveness of immune cells in vitro to both LPS and IgGIC, resulting in absence of acute lung injury after intratracheal administration of LPS or intrapulmonary immune complex deposition. In summary, we describe that TLR4 and FcγRIII pathways are structurally and functionally connected. These findings provide new insights of the interplay between innate and adaptive immunity, which closely interact with each other at the receptor level and post receptor signaling pathways.