FcγR-TLR Cross-Talk Enhances TNF Production by Human Monocyte-Derived DCs via IRF5-Dependent Gene Transcription and Glycolytic Reprogramming.

Willianne Hoepel,Melissa Newling,Lathees Sritharan,Ivo S Hansen,Martien L Kapsenberg,Bart Everts,Lisa T C Vogelpoel,Dominique L P Baeten,Jeroen Den Dunnen

doi:10.3389/fimmu.2019.00739

Abstract

Antigen-presenting cells (APCs) such as dendritic cells (DCs) are crucial for initiation of adequate inflammatory responses, which critically depends on the cooperated engagement of different receptors. In addition to pattern recognition receptors (PRRs), Fc gamma receptors (FcγRs) have recently been identified to be important in induction of inflammation by DCs. FcγRs that recognize IgG immune complexes, which are formed upon opsonization of pathogens, induce pro-inflammatory cytokine production through cross-talk with PRRs such as Toll-like receptors (TLRs). While the physiological function of FcγR-TLR cross-talk is to provide protective immunity against invading pathogens, undesired activation of FcγR-TLR cross-talk, e.g., by autoantibodies, also plays a major role in the development of chronic inflammatory disorders such as rheumatoid arthritis (RA). Yet, the molecular mechanisms of FcγR-TLR cross-talk are still largely unknown. Here, we identified that FcγR-TLR cross-talk-induced cytokine production critically depends on activation of the transcription factor interferon regulatory factor 5 (IRF5), which results from induction of two different pathways that converge on IRF5 activation. First, TLR stimulation induced phosphorylation of TBK1/IKKε, which is required for IRF5 phosphorylation and subsequent activation. Second, FcγR stimulation induced nuclear translocation of IRF5, which is essential for gene transcription by IRF5. We identified that IRF5 activation by FcγR-TLR cross-talk amplifies pro-inflammatory cytokine production by increasing cytokine gene transcription, but also by synergistically inducing glycolytic reprogramming, which is another essential process for induction of inflammatory responses by DCs. Combined, here we identified IRF5 as a pivotal component of FcγR-TLR cross-talk in human APCs. These data may provide new potential targets to suppress chronic inflammation in autoantibody-associated diseases that are characterized by undesired or excessive FcγR-TLR cross-talk, such as RA, systemic sclerosis, and systemic lupus erythematous.

Highlights

Protection against different classes of pathogens requires the activation of antigen-presenting cells (APCs) such as dendritic cells (DCs)
We identified that FcγR-Toll-like receptors (TLRs) cross-talk-induced cytokine production critically depends on activation of the transcription factor interferon regulatory factor 5 (IRF5), which results from collaborative IRF5 activation by both FcγRs and TLRs
We hypothesized a role for IRF5, since this transcription factor is known to be involved in enhancing TNF transcription [10,11,12,13,14], is highly expressed in human myeloid Antigen-presenting cells (APCs) [15], and since IRF5 polymorphisms are a known risk factor for several autoimmune diseases [16,17,18,19,20,21,22]

Summary

Introduction

Protection against different classes of pathogens requires the activation of antigen-presenting cells (APCs) such as dendritic cells (DCs). A crucial step for shaping both innate and adaptive immunity by DCs is the production of various pro-inflammatory cytokines. DCs produce these cytokines upon detection of pathogens or endogenous danger signals via activation of different families of receptors, which collectively are referred to as pattern recognition receptors (PRRs). It has become clear that the family of Fc gamma receptors (FcγRs), which are receptors for the Fc region of immunoglobulin G (IgG), play an important role in the induction of cytokines by DCs. While individual stimulation of FcγRs elicits little cytokine production, FcγRs synergize with PRRs such as TLRs to strongly but selectively amplify pro-inflammatory cytokine production. FcγRs synergize with TLRs that are expressed both intracellular (TLR3, TLR7/8) and extracellular (TLR2, TLR4, TLR5), as well as other receptors such as NLRs and particular cytokine receptors [1, 2]. Modulation of cytokine production by FcγRs thereby tailors immune responses to the immunological context [3, 4]

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Results

Conclusion