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 3

Expression of CCR2 on CD1c+ cDC associates with depletion of CD64hi-activated cells from the blood of patients with RA.

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Expression of CCR2 on CD1c+ cDC associates with depletion of CD64hi-acti...
(A and C) Heatmaps reflecting log2FC in the transcription of inflammatory cytokines downstream TLR and inflammasome (A) or the indicated chemokine receptors (C) in circulating CD1c+ cDC (blue bars), CD141+ cDC (red bars), and Mo (cyan bars) from peripheral blood (PB) of n = 4 patients with RA versus n = 4 healthy controls. Size of yellow circles represents different levels of statistical significance. (B) qPCR analysis of expression of some of the cytokines identified in A relative to β-actin levels in PB CD1c+ cDC (upper plots) and Mo (lower plots) from n = 4 healthy controls (HC) compared with n = 5 patients with RA. (D) Proportions of total CCR2hi cells included in the CD1c+ cDC from the blood of n = 20 patients with RA and n = 17 HC. Statistical significance was calculated using a 2 tailed Mann Whitney U test. (E) Proportions of CD64+ cells present on gated CCR2lo or CCR2hi subpopulations of CD1c+ cDC from the blood of patients with RA. (F) Proportions of CCR2+ cell from synovial fluid (SF) Mo and CD1c+ and CD141+ cDC from patients with RA (n = 4, red). Data represent mean and SEM values. **P < 0.01.