Histone Deacetylase 3-Mediated Inhibition of microRNA-19a-3p Facilitates the Development of Rheumatoid Arthritis-Associated Interstitial Lung Disease

Abstract

Histone deacetylase (HDAC) has been implicated in rheumatoid arthritis (RA) progression. We investigated the roles of histone deacetylase 3 (HDAC3) involved in RA-associated interstitial lung disease (ILD) fibrosis. Firstly, we measured the expression of HDAC3 and interleukin 17 receptor A (IL17RA) in lung tissue samples from normal controls, idiopathic pulmonary fibrosis (IPF) patients, and RA-ILD patients. Next, chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay were employed to detect the interaction between HDAC3 and microRNA-19a-3p (miR-19a-3p) and between miR-19a-3p and IL17RA. Further, immunohistochemistry was used to localize HDAC3 and IL17RA expression in lung tissues. Additionally, functional assays were conducted followed by expression determination of HDAC3, miR-19a-3p, and IL17RA with reverse transcription quantitative PCR (RT-qPCR) and Western blot analysis. The effect of HDAC3 on RA-ILD in the constructed RA-ILD mouse model was also studied based on arthritis assessment. We found overexpressed HDAC3 and IL17RA as well as silenced miR-19a-3p in RA-ILD mouse model and RA-ILD patients. In the mouse model, HDAC3 downregulated miR-19a-3p in lung fibroblasts to promote the progression of RA-ILD fibrosis. In lung fibroblasts of RA-ILD mice, IL17RA was a target gene of miR-19a-3p. miR-19a-3p negatively regulated IL17RA, thereby increasing the expression of fibrosis markers, COL1A1, COL3A1, and FN, in lung fibroblasts of mice. Taken together, HDAC3 upregulated IL17RA expression by targeting miR-19a-3p to facilitate the RA-ILD fibrosis development, which sheds light on a new HDAC3/miR-19a-3p/IL17RA axis functioning in RA-ILD fibrosis.

State of the Art in Idiopathic Pulmonary Fibrosis

“…Further, in agreement with various reports about expression patterns and functions of Class I enzymes, HDAC1, -2, and -3 indicated a dominant nuclear expression in the abovementioned cell types, whereas HDAC8 indicated cytoplasmic as well as nuclear localisation [165]. Further, HDAC2 and HDAC3 have been observed to be upregulated in various rodent models of pulmonary fibrosis [251,272], with predominant localisation in fibrotic lesions and lung fibroblasts [163,258,273].…”

“…Using an RA-ILD mouse model, HDAC3 downregulated miR-19a-3p expression in the lung fibroblasts of these mice, which resulted in increased IL17/IL17RA signalling and ECM protein expression, an effect that was abrogated by overexpression of miR-19a-3p or siRNA-mediated Il17ra or Hdac3 silencing. Of note, delivery of Hdac3-targeting siRNA to RA-ILD mice attenuated lung fibrosis in mice in vivo [273].…”

“…Moreover, HDAC3 has also been reported to negatively regulate miR-19a-3p to increase interleukin 17 receptor A (IL17RA) expression in rheumatoid arthritis (RA)associated interstitial lung disease (ILD) [273]. Interestingly, both HDAC3 and IL17RA were found to be much more upregulated in the lung tissues of RA-ILD patients than in patients with IPF versus healthy controls.…”

Screening and identification of key microRNAs and regulatory pathways associated with the renal fibrosis process

“…64,65 In addition, miR-19a-3p repressed the interleukin 17 receptor A (IL17RA) gene in mouse lung fibroblasts, which upregulated the fibrosis markers COL1A1, COL3A1 and FN. 66 It also inhibits epithelial mesenchymal transition (EMT) and ECM deposition. 67 MiR-379-5p is closely related to liver fibrosis 68 and renal fibrosis during diabetic nephropathy.…”

Resveratrol Ameliorates Fibrosis in Rheumatoid Arthritis-Associated Interstitial Lung Disease via the Autophagy–Lysosome Pathway

“…Some drugs may provide hope for the treatment of RA-ILD, including immunomodulators, such as mycophenolate and rituximab, and newly studied antifibrotic agents [ 7 ]. However, there is still little high-quality evidence to guide the treatment of RA-ILD [ 8 , 9 ].…”