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, Alberto Benguría, Raquel Largo, Diego Calzada‐Fraile, O. V. Popova, Ildefonso Sánchez‐Cerrillo, Ilya Tsukalov, Roberto Moreno‐Vellisca, Hortensia de la Fuente, Gabriel Herrero‐Beaumont, Almudena R. Ramiro, Francisco Sánchez‐Madrid, Santos Castañeda, Ana Dopazo, Isidoro González‐Álvaro, Enrique Martín‐Gayo
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.