Scleroderma (systemic sclerosis, SSc) is a complex autoimmune disease caused by progressive fibrotic replacement of normal tissue architecture, a progressive and ultimately fatal process that currently has no cure. Although dysregulation of microRNAs (miRNAs) is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in SSc is unclear. In comparison with the normal skin tissues, miRNAs were aberrantly expressed in limited cutaneous scleroderma and diffuse cutaneous scleroderma skin tissues. We also identified miRNAs whose expressions were correlated with SSc fibrosis: miR-21, miR-31, miR-146, miR-503, miR-145, and miR-29b were predicted to be involved. This study further confirmed that miR-21 was increased whereas miR-145 and miR-29b were decreased both in the skin tissues and fibroblasts. As predicted target genes, SMAD7, SAMD3, and COL1A1 were regulated by these miRNAs. After stimulation with transforming growth factor β, the expression of miR-21 was increased and that of SMAD7 mRNA was decreased. MiR-145 was upregulated whereas the mRNA level of SMAD3 was downregulated. The downregulation of miR-29b was correlated with the upregulation of COL1A1 mRNA. MiRNAs might play an important role in the pathogenesis of SSc and suggest a potential therapy.

Uncontrolled fibrosis in multiple organs is the main cause of death in systemic sclerosis (SSc), and transforming growth factor-β (TGF-β) activation plays a fundamental role in the process. Our previous study demonstrated that miR-21 was significantly up-regulated in SSc fibroblasts. Here, we found that TGF-β regulated the expression of miR-21 and fibrosis-related genes, and decreased Smad7 expression. Over-expression of miR-21 in fibroblasts decreased the levels of Smad7, whereas knockdown of miR-21 increased its expression. Further study using a reporter gene assay demonstrated Smad7 was a direct target of miR-21. Similar to human SSc, the expression of miR-21 increased in the bleomycin induced skin fibrosis. Inhibition of fibrosis by treatment with anti-fibrosis drug bortezomib restored the levels of miR-21 and Smad7. MiR-21 may function in an amplifying circuit to enhance TGF-β signaling events in SSc fibrosis, and suggesting that miR-21 may act as a potential therapeutic target.

SUMMARY The outbreak of coronavirus disease 2019 (COVID-19) in December 2019 in Wuhan, China, introduced the third highly pathogenic coronavirus into humans in the 21st century. Scientific advance after the severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic and Middle East respiratory syndrome coronavirus (MERS-CoV) emergence enabled clinicians to understand the epidemiology and pathophysiology of SARS-CoV-2. In this review, we summarize and discuss the epidemiology, clinical features, and virology of and host immune responses to SARS-CoV, MERS-CoV, and SARS-CoV-2 and the pathogenesis of coronavirus-induced acute respiratory distress syndrome (ARDS). We especially highlight that highly pathogenic coronaviruses might cause infection-associated hemophagocytic lymphohistiocytosis, which is involved in the immunopathogenesis of human coronavirus-induced ARDS, and also discuss the potential implication of hemophagocytic lymphohistiocytosis therapeutics for combating severe coronavirus infection.

It was recently demonstrated that the cholinergic anti-inflammatory pathway can modulate host inflammatory responses via cholinergic mediators or via electrical stimulation of the vagus nerve. Here, we investigated whether nicotine, a selective cholinergic agonist, plays any anti-inflammatory role in rheumatoid arthritis fibroblast-like synoviocytes (FLS). We observed that low concentrations (0.1-100 μM) of nicotine did not affect FLS viability in lactate dehydrogenase release test or the MTT assay. Nicotine at concentrations of 0.1-10 μM dose reduced the protein and mRNA expression of IL-6 and IL-8 induced by tumor necrosis factor-α (TNFα). Nicotine also inhibited nuclear factor (NF)-κB (p65) translocation from the cytoplasm to the nucleus, based on Western blotting and immunocytochemical analysis. In conclusion, nicotine can inhibit the TNFα dependant inflammatory pathway in synoviocytes by suppressing the activation of the NF-κB pathway.

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