Background/Purpose: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is associated with interstitial lung disease (ILD), which often represents rapidly progressive course and fatal outcomes. Circulating levels of ferritin were remarkably increased in patients with anti-MDA5-associated ILD, especially in those with rapidly progressive ILD, suggesting involvement of monocyte/macrophage activation in the pathogenic process. However, stimuli that trigger activation of monocytes/macrophages in anti-MDA5-associated ILD still remain unknown. In this study, we investigated molecules and pathways involved in activated monocytes in circulation from patients with anti-MDA5-associated ILD, using microarray expression profiling combined with the integrated miRNA-mRNA association analysis.

Methods: We first examined comprehensive expression profiling of mRNA and miRNA by a microarray system using circulating CD14⁺ monocytes from 3 untreated patients with anti-MDA5-associated ILD and 3 healthy controls (HCs). Then, integrated miRNA-mRNA association analysis was conducted to identify molecules related to disease pathways and their regulator effect networks using Ingenuity Pathway Analysis (IPA) system. The relevant gene expression levels were validated by real-time PCR using additional circulating monocyte samples obtained from 5 untreated patients with anti-MDA5-associated ILD, 5 patients with anti-aminoacyl tRNA synthetase (ARS)-associated ILD, and 5 HCs.

Results: Twenty-six significant matched pairs of differentially down-regulated miRNA and up-regulated mRNA were identified by IPA, and 6 relevant genes associated with disease pathways included IFIT2, IFIT3, MX1, IRF7, CCL2 and CLU. The major relevant genes of our dataset were type 1 interferon (IFN)-inducible genes. The regulator effect network analysis identified 5 predicted upstream regulators, including IFN-β, toll-like receptor (TLR) 3, TLR7, TLR9, and SPI1. Anti-viral infection pathway was identified as the predicted downstream effect involved with those 6 relevant genes. The mRNA expressions levels of 6 genes associated with disease pathways were confirmed to be higher in patients with anti-MDA5-associated ILD than in those with anti-ARS-associated ILD or HCs, and were declined after immunosuppressive treatment in patients with anti-MDA5-associated ILD.

Conclusion: Anti-viral proinflammatory pathways are activated in circulating monocytes from patients with anti-MDA5-associated ILD, suggesting roles of viral infection in triggering this devastating condition.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-viral-proinflammatory-phenotype-in-circulating-monocytes-from-patients-with-anti-melanoma-differentiation-associated-gene-5-antibody-associated-interstitial-lung-disease/