Yoon Bo Ruem, Yoo Su-Jin, Choi Yeon ho, Chung Yeon-Ho, Kim Jinhyun, Yoo In Seol, Kang Seong Wook, Lee Won-Woo
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.
Department of Internal Medicine, Chungnam National University School of Medicine, Daejon, Korea.
PLoS One. 2014 Oct 17;9(10):e109775. doi: 10.1371/journal.pone.0109775. eCollection 2014.
Monocytes function as crucial innate effectors in the pathogenesis of chronic inflammatory diseases, including autoimmunity, as well as in the inflammatory response against infectious pathogens. Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression. Although accumulating evidence suggests distinct functions of monocyte subsets in inflammatory conditions, their pathogenic roles in autoimmune diseases remain unclear. Thus, we investigated the phenotypic and functional characteristics of monocytes derived from synovial fluid and peripheral blood in RA patients in order to explore the pathogenic roles of these cells. In RA patients, CD14+CD16+, but not CD14dimCD16+, monocytes are predominantly expanded in synovial fluid and, to a lesser degree, in peripheral blood. Expression of co-signaling molecules of the B7 family, specifically CD80 and CD276, was markedly elevated on synovial monocytes, while peripheral monocytes of RA and healthy controls did not express these molecules without stimulation. To explore how synovial monocytes might gain these unique properties in the inflammatory milieu of the synovial fluid, peripheral monocytes were exposed to various stimuli. CD16 expression on CD14+ monocytes was clearly induced by TGF-β, although co-treatment with IL-1β, TNF-α, or IL-6 did not result in any additive effects. In contrast, TLR stimulation with LPS or zymosan significantly downregulated CD16 expression such that the CD14+CD16+ monocyte subset could not be identified. Furthermore, treatment of monocytes with IFN-γ resulted in the induction of CD80 and HLA-DR expression even in the presence of TGF-β. An in vitro assay clearly showed that synovial monocytes possess the unique capability to promote Th1 as well as Th17 responses of autologous peripheral CD4 memory T cells. Our findings suggest that the cytokine milieu of the synovial fluid shapes the unique features of synovial monocytes as well as their cardinal role in shaping inflammatory T-cell responses in RA.
单核细胞在包括自身免疫性疾病在内的慢性炎症性疾病的发病机制以及针对感染性病原体的炎症反应中起着关键的固有效应器作用。人类单核细胞具有异质性，可根据CD14和CD16的表达分为三个不同的亚群。尽管越来越多的证据表明单核细胞亚群在炎症条件下具有不同的功能，但其在自身免疫性疾病中的致病作用仍不清楚。因此，我们研究了类风湿关节炎（RA）患者滑液和外周血来源的单核细胞的表型和功能特征，以探讨这些细胞的致病作用。在RA患者中，CD14+CD16+单核细胞而非CD14dimCD16+单核细胞在滑液中显著扩增，在外周血中扩增程度较小。B7家族共信号分子，特别是CD80和CD276，在滑膜单核细胞上的表达明显升高，而RA患者和健康对照的外周单核细胞在未受刺激时不表达这些分子。为了探究滑膜单核细胞如何在滑液的炎症环境中获得这些独特特性，将外周单核细胞暴露于各种刺激下。TGF-β可明显诱导CD14+单核细胞上CD16的表达，尽管与IL-1β、TNF-α或IL-6共同处理未产生任何累加效应。相反，用LPS或酵母聚糖进行Toll样受体（TLR）刺激可显著下调CD16表达，以至于无法识别CD14+CD16+单核细胞亚群。此外，即使存在TGF-β，用干扰素-γ处理单核细胞也会导致CD80和HLA-DR表达的诱导。体外试验清楚地表明，滑膜单核细胞具有促进自身外周CD4记忆T细胞的Th1以及Th17反应的独特能力。我们的研究结果表明，滑液的细胞因子环境塑造了滑膜单核细胞的独特特征及其在RA中塑造炎症性T细胞反应的核心作用。
