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Direct tissue-sensing reprograms TLR4⁺ Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients.

ABSTRACT: CD4⁺ T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4⁺ T cells pathogenic functions. Here, we identified a TLR4⁺ follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. TLR4⁺ T cells possess a two-pronged pathogenic activity whereby direct TLR4⁺ engagement by endogenous ligands in the arthritic joint reprograms them from an IL-21 response, known to sponsor antibody production towards an IL-17 inflammatory program recognized to fuel tissue damage. Ex vivo, synovial fluid TLR4⁺ T cells produced IL-17, but not IL-21. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Mechanistically, we unveiled that T-cell HLA-DR regulates their TLR4 expression. TLR4⁺ T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program.

SUBMITTER: Amaral-Silva D

PROVIDER: S-EPMC8476501 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Direct tissue-sensing reprograms TLR4+ Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients.

Amaral-Silva Daniela D Gonçalves Rute R Torrão Rita C RC Torres Rita R Falcão Sandra S Gonçalves Maria João MJ Araújo Maria Paula MP Martins Maria José MJ Lopes Carina C Neto Agna A Marona José J Costa Tiago T Castelão Walter W Silva Ana Bento AB Silva Inês I Lourenço Maria Helena MH Mateus Margarida M Gonçalves Nuno Pina NP Manica Santiago S Costa Manuela M Pimentel-Santos Fernando M FM Mourão Ana Filipa AF Branco Jaime C JC Soares Helena H

Communications biology 20210927 1

CD4+ T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4+ T cells pathogenic functions. Here, we identified a TLR4+ follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. TLR4+ T cells possess a two-pronged pathogenic activity whereby direct TLR4+ engagement by endogenous ...[more]

PMID: 34580414

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Project description:Background and aimsGM-CSF-dependent macrophage polarization has been demonstrated in rheumatoid arthritis (RA). Our aim was to seek diagnostic/prognostic biomarkers for undifferentiated arthritis (UA) by analyzing GM-CSF expression and source, macrophage polarization and density in joints of patients with UA evolving to RA or PsA compared with established RA or PsA, respectively.MethodsSynovial tissue (ST) from patients with UA evolving to RA (UA>RA, n=8), PsA (UA>PsA, n=9), persistent UA (UA, n=16), established RA (n=12) and PsA (n=10), and healthy controls (n=6), were analyzed. Cell source and quantitative expression of GM-CSF and proteins associated with pro-inflammatory (GM-CSF-driven) and anti-inflammatory (M-CSF-driven) macrophage polarization (activin A, TNFα, MMP12, and CD209, respectively) were assessed in ST CD163+ macrophages by multicolor immunofluorescence. GM-CSF and activin A levels were also quantified in paired synovial fluid samples. CD163+ macrophage density was determined in all groups by immunofluorescence.ResultsSynovial stromal cells (FAP+ CD90+ fibroblast, CD90+ endothelial cells) and CD163+ sublining macrophages were the sources of GM-CSF. ST CD163+ macrophages from all groups expressed pro-inflammatory polarization markers (activin A, TNFα, and MMP12). Expression of the M-CSF-dependent anti-inflammatory marker CD209 identified two macrophage subsets (CD163+ CD209high and CD163+ CD209low/-). CD209+ macrophages were more abundant in ST from healthy controls and PsA patients, although both macrophage subtypes showed similar levels of pro-inflammatory markers in all groups. In paired synovial fluid samples, activin A was detected in all patients, with higher levels in UA>RA and RA, while GM-CSF was infrequently detected. ST CD163+ macrophage density was comparable between UA>RA and UA>PsA patients, but significantly higher than in persistent UA.ConclusionsGM-CSF is highly expressed by sublining CD90+ FAP+ synovial fibroblasts, CD90+ activated endothelium and CD163+ macrophages in different types of arthritis. The polarization state of ST macrophages was similar in all UA and established arthritis groups, with a predominance of pro-inflammatory GM-CSF-associated markers. CD163+ macrophage density was significantly higher in the UA phases of RA and PsA compared with persistent UA. Taken together, our findings support the idea that GM-CSF is a strong driver of macrophage polarization and a potential therapeutic target not only in RA but also in PsA and all types of UA.

Dataset Information

Direct tissue-sensing reprograms TLR4⁺ Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients.

Publications

Direct tissue-sensing reprograms TLR4<sup>+</sup> Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients.

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