The individual contribution of specific myeloid subsets such as CD1c+ conventional dendritic cells (cDC) to perpetuation of Rheumatoid Arthritis (RA) pathology remains unclear. In addition, the specific innate sensors driving pathogenic activation of CD1c+ cDCs in RA patients and their functional implications have not been characterized. Here, we assessed phenotypical, transcriptional and functional characteristics of CD1c+ and CD141+ cDCs and monocytes from the blood and synovial fluid of RA patients. Increased levels of CCR2 and the IgG receptor CD64 on circulating CD1c+ cDC associated with the presence of this DC subset in the synovial membrane in RA patients. Moreover, synovial CD1c+ cDCs are characterized by increased expression of proinflammatory cytokines and high abilities to induce pathogenic IFNγ+IL-17+ CD4+ T cells in vitro. Finally, we identified the crosstalk between Fcγ Receptors and NLRC4 as a new potential molecular mechanism mediating pathogenic activation, CD64 upregulation and functional specialization of CD1c+ cDCs in response to dsDNA-IgG in RA patients.E.M.G. was supported by Comunidad de Madrid Talento Program (2017-T1/BMD5396), Ramón y Cajal Program (RYC2018-024374-I), the MINECO RETOS program
(RTI2018-097485-A-I00), La Caixa Foundation (HR20-00218), CIBERINF (CB21/13/00107) and the TV3 Marató (REDINCOV). C.D.A. was supported by
Comunidad de Madrid Talento Program (2017-T1/BMD-5396). M.C.M was supported
by the NIH (R21AI140930). HR17-00016 grant from “La Caixa Banking Foundation to
F.S.M also supported the study. D.C-F. is supported by the Fellowship “la Caixa”
Foundation LCF/BQ/DR19/11740010. A.T.M. was supported by a PhD fellowship from
the Autonomous Region of Madrid (PEJD-2019-PRE/BMD-16851) and the
RD21/0002/0027 grant. R.L. and G.H.B. were supported by PI18/00261 AND
PI20/00349 grants from Ministerio de Ciencia e Innovación and Instituto de Salud Carlos
III, respectively. O.P. was supported by the TV3 Marató (REDINCOV) and I.T. was
funded by grant for the promotion of research studies master-UAM 2021. S.C. was
supported by PI21/01474 grant from the Instituto de Salud Carlos III and co-funded by
The European Regional Development Fund (ERDF). I.G.A was supported by
RD21/0002/0027 and PI21/00526 grants from the Spanish MINECO and Instituto de
Salud Carlos III and co-funded by The European Regional Development Fund (ERDF)
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