Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.
Rheumatology (Oxford). 2022 Feb 2;61(2):806-814. doi: 10.1093/rheumatology/keab371.
To evaluate upstream and downstream regulators leading to macrophage activation and subsequent cytokine storm in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-associated interstitial lung disease (ILD).
We conducted an integrated miRNA-mRNA association analysis using circulating monocytes from 3 patients with anti-MDA5-associated ILD and 3 healthy controls and identified disease pathways and a regulator effect network by Ingenuity Pathway Analysis (IPA). The expression of relevant genes and proteins was verified using an independent validation cohort, including 6 patients with anti-MDA5-associated ILD, 5 with anti-aminoacyl tRNA synthetase antibody-associated ILD, and 6 healthy controls.
IPA identified 26 matched pairs of downregulated miRNA and upregulated mRNAs and revealed that canonical pathways mediated by type I IFN signalling and C-C motif ligand 2 (CCL2) were responsible for the pathogenic process (P < 0.05 for all pathways). The regulatory network model identified IFN-β; Toll-like receptors 3, 7, and 9; and PU.1 as upstream regulators, while the downstream effect of this network converged at the inhibition of viral infection. mRNA and protein expression analysis using validation cohort showed a trend towards the increased expression of relevant molecules identified by IPA in patients with anti-MDA5-associated ILD compared with those with anti-aminoacyl tRNA synthetase antibody-associated ILD or healthy controls. The expression of all relevant genes in monocytes and serum levels of CCL2 and IFN-β declined after treatment in survivors with anti-MDA5-associated ILD.
An antiviral proinflammatory network orchestrated primarily by activated monocytes/macrophages might be responsible for cytokine storm in anti-MDA5-associated ILD.
评估导致抗黑色素瘤分化相关基因 5（MDA5）抗体相关性间质性肺病（ILD）患者巨噬细胞活化和随后细胞因子风暴的上游和下游调节因子。
我们使用 3 例抗 MDA5 相关性ILD 患者和 3 例健康对照者的循环单核细胞进行了 miRNA-mRNA 关联分析，并通过 Ingenuity Pathway Analysis（IPA）鉴定了疾病途径和调节因子效应网络。使用包括 6 例抗 MDA5 相关性ILD、5 例抗氨酰基 tRNA 合成酶抗体相关性ILD 和 6 例健康对照者的独立验证队列，验证了相关基因和蛋白的表达。
IPA 鉴定了 26 对下调的 miRNA 和上调的 mRNAs，结果表明，I 型 IFN 信号和 C-C 基序配体 2（CCL2）介导的经典途径是导致发病机制的原因（所有途径的 P<0.05）。调控网络模型确定 IFN-β；Toll 样受体 3、7 和 9；和 PU.1 为上游调节剂，而该网络的下游效应则集中在抑制病毒感染上。使用验证队列的 mRNA 和蛋白表达分析显示，与抗氨酰基 tRNA 合成酶抗体相关性ILD 患者或健康对照者相比，抗 MDA5 相关性ILD 患者中 IPA 鉴定的相关分子表达呈增加趋势。在抗 MDA5 相关性ILD 幸存者中，单核细胞中所有相关基因的表达以及血清中 CCL2 和 IFN-β 的水平在治疗后均下降。
由激活的单核细胞/巨噬细胞主要调控的抗病毒炎症网络可能是抗 MDA5 相关性ILD 中细胞因子风暴的原因。
