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FcγR-TLR Cross-Talk Enhances TNF Production by Human Monocyte-Derived DCs via IRF5-Dependent Gene Transcription and
Willianne Hoepel1,2, Melissa Newling1,2, Lisa T C Vogelpoel2
1Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands.
Frontiers in Immunology
|April 27, 2019
Summary
Interferon regulatory factor 5 (IRF5) is key to Fc gamma receptor (FcγR)-Toll-like receptor (TLR) cross-talk in antigen-presenting cells (APCs). This interaction amplifies inflammation by boosting cytokine production and reprogramming metabolism, offering targets for autoimmune diseases.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Antigen-presenting cells (APCs), including dendritic cells (DCs), initiate inflammatory responses via receptor engagement.
- Fc gamma receptors (FcγRs) and pattern recognition receptors (PRRs), like Toll-like receptors (TLRs), cooperate in DC-mediated inflammation.
- Dysregulated FcγR-TLR cross-talk contributes to chronic inflammatory diseases such as rheumatoid arthritis (RA).
Purpose of the Study:
- To elucidate the molecular mechanisms underlying FcγR-TLR cross-talk in human APCs.
- To identify key transcription factors involved in FcγR-TLR-induced inflammatory responses.
- To explore the role of IRF5 in amplifying cytokine production and metabolic reprogramming during FcγR-TLR cross-talk.
Main Methods:
- Investigated the role of transcription factor IRF5 in FcγR-TLR cross-talk.
- Analyzed TLR-induced phosphorylation of TBK1/IKKε and its effect on IRF5.
- Studied FcγR-induced nuclear translocation of IRF5 and its impact on gene transcription and glycolytic reprogramming.
Main Results:
- FcγR-TLR cross-talk-induced cytokine production critically depends on interferon regulatory factor 5 (IRF5) activation.
- TLR stimulation leads to IRF5 phosphorylation via TBK1/IKKε, while FcγR stimulation induces IRF5 nuclear translocation.
- IRF5 amplifies inflammation by increasing cytokine gene transcription and synergistically inducing glycolytic reprogramming in DCs.
Conclusions:
- IRF5 is a pivotal component of FcγR-TLR cross-talk in human APCs.
- IRF5 activation enhances pro-inflammatory cytokine production and metabolic reprogramming.
- Targeting IRF5 may offer therapeutic strategies for chronic inflammatory and autoimmune diseases.
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