Monocyte/Macrophage Abnormalities Specific to Rheumatoid Arthritis Are Linked to miR-155 and Are Differentially Modulated by Different TNF Inhibitors
Monocyte/Macrophage Abnormalities Specific to Rheumatoid Arthritis Are Linked to miR-155 and Are Differentially Modulated by Different TNF Inhibitors
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DOI：
10.4049/jimmunol.1900386
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发表时间：
2019-10-01
影响因子：
4.4
通讯作者：
Mariette, Xavier
中科院分区：
文献类型：
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作者：
Paoletti, Audrey;Rohmer, Julien;Mariette, Xavier
类风湿关节炎(RA)患者的促炎巨噬细胞和miR-155增加。我们研究了类风湿关节炎患者外周血单核细胞膜上肿瘤坏死因子(Mtnf)的表达、巨噬细胞极化、miR-155的表达以及抗肿瘤坏死因子对这些生物标志物的影响。研究了67例RA患者和109例正常对照(55例健康人，54例脊椎关节炎和结缔组织病患者)。分离单核细胞，在有或无抗肿瘤坏死因子的作用下分化为巨噬细胞。类风湿性关节炎患者单核细胞上mtnf表达增加，而其他炎症性疾病患者外周血单核细胞mtnf表达增加，且与疾病活动性相关。在人血清AB或M-CSF作用下，只有RA的单核细胞有向M2样巨噬细胞分化的缺陷，并倾向于向参与滑膜炎症的M1样巨噬细胞优先成熟。这种缺陷与mtnf的表达有关，并可被抗肿瘤坏死因子单抗部分逆转，但不能被肿瘤坏死因子可溶性受体逆转。除阿达单抗治疗组外，M2-巨噬细胞的MIR-155均升高。转染miR-155的健康单核细胞可诱导M2样标记物的减少，而转染antagomir-155的RA单核细胞可恢复M2样极化。单核细胞分化为M2样巨噬细胞的缺陷与miR-155的升高有关，并与单核细胞上mtnf的增加相关，可能在RA的发病中起关键作用。抗肿瘤坏死因子的单抗，而不是肿瘤坏死因子可溶性受体，部分修复了这一缺陷。
Proinflammatory macrophages and miR-155 are increased in patients with rheumatoid arthritis (RA). We studied membrane TNF (mTNF) expression on blood monocytes, polarization into macrophages, miR-155 expression, and the effect of anti-TNF on these biomarkers in RA patients. Sixty-seven RA patients and 109 controls (55 healthy, 54 with spondyloarthritis and connective tissue diseases) were studied. Monocytes were isolated and differentiated into macrophages with or without anti-TNF. mTNF expression was increased on monocytes from RA patients, but not from other inflammatory diseases, correlated with disease activity. Under human serum AB or M-CSF, only monocytes from RA had a defect of differentiation into M2-like macrophages and had a propensity for preferential maturation toward M1-like macrophages that contributed to synovial inflammation. This defect was correlated to mTNF expression and was partially reversed by monoclonal anti-TNF Abs but not by the TNF soluble receptor. miR-155 was increased in M2-macrophages except in adalimumab-treated patients. Transfection of healthy monocytes with miR-155 induced a decrease in M2-like markers, and transfection of RA monocytes with antagomir-155 allowed restoration of M2-like polarization. Defect in differentiation of monocytes into M2-like-macrophages linked to increased miR-155 and correlated with increased mTNF on monocytes could play a key role in RA pathogenesis. Monoclonal anti-TNF Abs but not the TNF soluble receptor partially restored this defect.