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

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.

<p>Integrated Gene Expression Profiling Analysis Reveals Probable Molecular Mechanism and Candidate Biomarker in Anti-TNFα Non-Response IBD Patients</p>

“…Thirdly, the FcγR signaling could cross-link to the Toll-like pathway greatly up-regulates pro-inflammatory chemokines transcriptional, and Toll-like pathway agonist could partially rescue lgG/FcγR induction of inflammation in the setting of deficient chemokines expression. 53,54 Furthermore, several studies have highlighted a link between TLR and FcγR costimulation and the induction of a Th17 polarizing and pathogenic macrophage phenotype, which is constant to the characteristic of IBD. [53][54][55] Taken together, FcγR stimulated by anti-commensal IgG signaling synergistic cooperating with toll-like pathway derives inappropriate inflammation in the gut, which might be crucial in the pathogenesis of nonresponse of anti-TNFα agents.…”

“…53,54 Furthermore, several studies have highlighted a link between TLR and FcγR costimulation and the induction of a Th17 polarizing and pathogenic macrophage phenotype, which is constant to the characteristic of IBD. [53][54][55] Taken together, FcγR stimulated by anti-commensal IgG signaling synergistic cooperating with toll-like pathway derives inappropriate inflammation in the gut, which might be crucial in the pathogenesis of nonresponse of anti-TNFα agents. These results suggest that the FcγR-TLR axis is responsible for the magnify reciprocal signaling, which ultimately impacts response status.…”

Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

“…FcγRs are known to induce signaling that critically depends on the kinase Syk (28,29). To determine whether we could counteract anti-Spike-induced immune activation, we blocked Syk using R406, the active component of the small molecule inhibitor fostamatinib, an FDA-and EMA-approved drug for treatment of immune thrombocytopenia (ITP) (30).…”

“…In addition to fostamatinib, also other drugs that target key molecules in FcγR signaling could be efficacious to counteract anti-Spike IgG-induced inflammation in COVID-19 patients. For example, the Sykdependent FcγR signaling pathway critically depends on the transcription factor IRF5 (15,28), which can be targeted using cell penetrating peptides (40). Furthermore, FcγR stimulation is known to induce metabolic reprogramming of human macrophages (28), which is also observed in COVID-19 patients (41), and therefore may provide additional targets for therapy.…”

Dysregulated Fcγ receptor IIa-induced cytokine production in dendritic cells of lupus nephritis patients

“…The amplification of IL‐1β upon FcγRIIa–TLR co‐stimulation is dependent upon signaling via the kinase Syk . Although both FcγRIIa and TLRs have been described to signal via Syk, IL‐1β amplification induced by FcγRIIa–TLR cross‐talk is specifically dependent upon FcγRIIa triggering . Therefore, we next determined whether Syk expression is increased in DCs of lupus nephritis patients.…”