NLRC4-mediated activation of CD1c+ DC contributes to perpetuation of synovitis in rheumatoid arthritis
Cristina Delgado-Arévalo, … , Isidoro González Álvaro, Enrique Martin-Gayo
Cristina Delgado-Arévalo, … , Isidoro González Álvaro, Enrique Martin-Gayo
Published October 4, 2022
Citation Information: JCI Insight. 2022;7(22):e152886. https://doi.org/10.1172/jci.insight.152886.
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Research Article Cell biology

NLRC4-mediated activation of CD1c+ DC contributes to perpetuation of synovitis in rheumatoid arthritis

Abstract

The individual contribution of specific myeloid subsets such as CD1c+ conventional DC (cDC) to perpetuation of rheumatoid arthritis (RA) pathology remains unclear. In addition, the specific innate sensors driving pathogenic activation of CD1c+ cDC in patients with RA and their functional implications have not been characterized. Here, we assessed phenotypical, transcriptional, and functional characteristics of CD1c+ and CD141+ cDC and monocytes from the blood and synovial fluid of patients with RA. Increased levels of CCR2 and the IgG receptor CD64 on circulating CD1c+ cDC was associated with the presence of this DC subset in the synovial membrane in patients with RA. Moreover, synovial CD1c+ cDC are characterized by increased expression of proinflammatory cytokines and high abilities to induce pathogenic IFN-γ+IL-17+CD4+ T cells in vitro. Finally, we identified the crosstalk between Fcγ receptors and NLRC4 as a potential molecular mechanism mediating pathogenic activation, CD64 upregulation, and functional specialization of CD1c+ cDC in response to dsDNA-IgG in patients with RA.

Authors

Cristina Delgado-Arévalo, Marta Calvet-Mirabent, Ana Triguero-Martínez, Enrique Vázquez de Luis, Alberto Benguría-Filippini, Raquel Largo, Diego Calzada-Fraile, Olga Popova, Ildefonso Sánchez-Cerrillo, Ilya Tsukalov, Roberto Moreno-Vellisca, Hortensia de la Fuente, Gabriel Herrero-Beaumont, Almudena Ramiro, Francisco Sánchez-Madrid, Santos Castañeda, Ana Dopazo, Isidoro González Álvaro, Enrique Martin-Gayo

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Figure 4

Inflammatory and functional profiles in circulating and synovial CD1c+ cDC from patients with RA.

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Inflammatory and functional profiles in circulating and synovial CD1c+ c...
(A) qPCR analysis of the indicated cytokines relative to β-actin levels in sorted populations from RA (n = 5) and CPPD-associated arthropathy (n = 3) synovial fluids (SF). (B) Representative FACS analysis of IFN-γ versus IL-17a expression on CD4+ T cells cultured for 5 days alone or in the presence of Mo, CD1c+, or CD141+ cDC from the SF of patients with RA. Proportions of total IL17+ and pathogenic IL-17a+IFN-γ+ CD4+ T cells are highlighted in black and red gates, respectively. (C) Quantification of proportions of pathogenic IL-17a+IFN-γ+CD4+ T cells induced under the conditions defined in B, from n = 9 HC. Statistical significance was calculated using 2-tailed Wilcoxon matched pairs signed rank test. *P < 0.05; ***P < 0.001. (D) Representative confocal microscopy images (original magnification, 40×/1.4-0.75) showing infiltrated HLA-DR+CD1c+ cells and HLA-DR-IL-17+ cells in close proximity in histological sections of synovial membrane from n = 6 patients with RA. Images showing coexpression with HLA-DR or without this marker are shown on the left and right, respectively.