JCI Insight (Nov 2022)

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

  • 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

Journal volume & issue
Vol. 7, no. 22

Abstract

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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.

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