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NLRC4 介导的 CD1c+ DC 的激活有助于类风湿关节炎滑膜炎症的持续存在。

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

机构信息

Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.

Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.

出版信息

JCI Insight. 2022 Nov 22;7(22):e152886. doi: 10.1172/jci.insight.152886.

DOI:10.1172/jci.insight.152886
PMID:36194479
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9746818/
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.

摘要

特定髓系细胞亚群（如 CD1c+常规树突状细胞（cDC））在类风湿关节炎（RA）病理中的个体贡献仍不清楚。此外，驱动 RA 患者 CD1c+cDC 致病性激活的特定先天传感器及其功能意义尚未得到表征。在这里，我们评估了 RA 患者血液和滑膜液中 CD1c+和 CD141+cDC 和单核细胞的表型、转录和功能特征。循环 CD1c+cDC 上 CCR2 和 IgG 受体 CD64 的水平升高与该 DC 亚群在 RA 患者滑膜膜中的存在有关。此外，滑膜 CD1c+cDC 的特征是表达更高水平的促炎细胞因子，并具有更高的体外诱导致病性 IFN-γ+IL-17+CD4+T 细胞的能力。最后，我们确定了 Fcγ 受体和 NLRC4 之间的串扰是一种潜在的分子机制，介导了致病性激活、CD64 上调以及 CD1c+cDC 的功能特化，以响应 RA 患者中的 dsDNA-IgG。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e133/9746818/1479fbe6d51f/jciinsight-7-152886-g076.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e133/9746818/7266a992cec6/jciinsight-7-152886-g073.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e133/9746818/6b2e4bb88465/jciinsight-7-152886-g074.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e133/9746818/bcb9ec564efb/jciinsight-7-152886-g075.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e133/9746818/1479fbe6d51f/jciinsight-7-152886-g076.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e133/9746818/df100d1f00d0/jciinsight-7-152886-g070.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e133/9746818/a2614bbf7f8e/jciinsight-7-152886-g071.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e133/9746818/2ce9e508b380/jciinsight-7-152886-g072.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e133/9746818/7266a992cec6/jciinsight-7-152886-g073.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e133/9746818/6b2e4bb88465/jciinsight-7-152886-g074.jpg
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