Vitamin D3 Attenuates Viral-Induced Inflammation and Fibrotic Responses in Bronchial Smooth Muscle Cells

Abstract

Toll-like receptor 3 (TLR3) activation by viral infections plays a key role in promoting inflammatory immune responses that contribute to pulmonary fibrosis in chronic inflammatory respiratory diseases. Vitamin D3 has been shown to be beneficial to patients with asthma and chronic obstructive pulmonary disease (COPD) through its anti-inflammatory and anti-fibrotic properties. Smooth muscle cells are one of the major contributors to airway remodeling in asthma and COPD. We therefore aimed to investigate the effect of vitamin D3 treatment on viral-induced TLR3 responses in Bronchial Smooth Muscle Cells (BSMCs) as a mechanism contributing to pulmonary fibrosis in asthma and COPD. Primary BSMCs from patients with asthma (n=4), COPD (n=4), and healthy control subjects (n=6) were treated with polyinosinic: polycytidylic acid (polyI:C), TLR3 agonist in the presence or absence of vitamin D3 (1,25D3). Here we report the mRNA expression and protein levels of pro-inflammatory and pro-fibrotic markers (IL-6, IFN-β1, CCL2/MCP-1, fibronectin 1 and type I collagen) among BSMCs groups: asthma, COPD, and healthy controls. We show that at the baseline, prior to polyI:C stimulation, asthma and COPD BSMCs presented increased pro-inflammatory and pro-fibrotic state compared to healthy control subjects, as measured by quantitative PCR and immunoassays (ELISA/Flow Cytometry. Ligation of TLR3 by polyI:C in BSMCs was associated with increased TLR3 mRNA expression, and 1,25D3 treatment significantly reduced its expression. In addition, 1,25D3 decreased the expression of IL-6, IFN-β1, CCL2, FN1 and COL1A1 induced by polyI:C in BSMCs. The regulatory effect of 1,25D3 treatment on polyI:C-stimulated BSMCs was further confirmed at protein levels. Our findings suggest that vitamin D3 attenuates TLR3 agonist-induced inflammatory and fibrotic responses in BSMCs and support the clinical relevance of vitamin D3 supplementation in patients with viral infections having chronic respiratory diseases, such as asthma and COPD.

Network pharmacology and bioinformatics to identify molecular mechanisms and therapeutic targets of Ruyi Jinhuang Powder in the treatment of monkeypox

“…A significant role of FN1 in anti-inflammatory mechanisms and related diseases has been extensively reported in the literature. [51][52][53] FN1 is highly expressed in nodular disease, a systemic inflammatory disease manifested by pulmonary involvement and erythema nodosum of the skin. [33] CDK2 is involved in cell cycle regulation and is generally considered important in cancer pathogenesis.…”

The role of gut microbiome in the complex relationship between respiratory tract infection and asthma

“…Excessive TLR3-mediated inflammation may play a key role in promoting asthma exacerbation and fibrosis, with bronchial smooth muscle cells (BSMCs) being one of the major contributors to asthma airway remodeling (Yang et al, 2017 ). Plesa et al ( 2021 ) indicate that vitamin D3 can attenuate TLR3 agonist-induced inflammation and fibrotic responses in BSMCs, exerting a protective effect in the development of worsened conditions associated with viral infections. These results support vitamin D3 supplementation in virus-infected asthma patients.…”

Recent advances in vitamin D implications in chronic respiratory diseases

“…Vitamin D has been shown to reduce proliferation, proinflammatory cytokines, matrix metalloproteinase (MMP) in airway smooth muscle cells [ 32 ], factors contributing to airway inflammation and remodeling. In another study, it was shown that vitamin D in airway smooth muscle cells attenuates TLR3 agonist-induced inflammatory and fibrotic responses by a viral antigen [ 37 ].…”