Impact of the Local Inflammatory Environment on Mucosal Vitamin D Metabolism and Signaling in Chronic Inflammatory Lung Diseases

Abstract

Vitamin D plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens. Evidence for this immunomodulatory and protective role is derived from observational studies showing an association between vitamin D deficiency, chronic airway diseases and respiratory infections, and is supported by a range of experimental studies using cell culture and animal models. Furthermore, recent intervention studies have now shown that vitamin D supplementation reduces exacerbation rates in vitamin D-deficient patients with chronic obstructive pulmonary disease (COPD) or asthma and decreases the incidence of acute respiratory tract infections. The active vitamin D metabolite, 1,25-dihydroxy-vitamin D (1,25(OH) 2 D), is known to contribute to the integrity of the mucosal barrier, promote killing of pathogens (via the induction of antimicrobial peptides), and to modulate inflammation and immune responses. These mechanisms may partly explain its protective role against infections and exacerbations in COPD and asthma patients. The respiratory mucosa is an important site of local 1,25(OH) 2 D synthesis, degradation and signaling, a process that can be affected by exposure to inflammatory mediators. As a consequence, mucosal inflammation and other disease-associated factors, as observed in e.g., COPD and asthma, may modulate the protective actions of 1,25(OH) 2 D. Here, we discuss the potential consequences of various disease-associated processes such as inflammation and exposure to pathogens and inhaled toxicants on vitamin D metabolism and local responses to 1,25(OH) 2 D in both immune-and epithelial cells. We furthermore discuss potential consequences of disturbed local levels of 25(OH)D and 1,25(OH) 2 D for chronic lung diseases. Additional insight into the relationship between disease-associated mechanisms and local effects of 1,25(OH) 2 D is expected to contribute to the design of future strategies aimed at improving local levels of 1,25(OH) 2 D and signaling in chronic inflammatory lung diseases.

Investigating the Potential for Ultraviolet Light to Modulate Morbidity and Mortality From COVID-19: A Narrative Review and Update

“…Other researchers have recently reviewed various others means through which vitamin D could limit the impacts of SARS-CoV-2 infection. These include its capacity to regulate autophagy and apoptosis, reduce cytokine hyperproduction and limit lung injury induced by viral infections ( 168 – 170 ). For people infected with human immunodeficiency virus, vitamin D may act as an adjuvant during retroviral therapy with some VDR alleles increasing susceptibility for infection with the human immunodeficiency virus ( 168 ).…”

“…Others hypothesize that vitamin D could combine effectively with interferon (IFN) to control SARS-CoV-2 infection, with vitamin D modulating the expression of IFN-stimulated genes during infection with hepatitis C virus or rhinovirus ( 171 ). Vitamin D may limit the proliferation and reduce innate inflammatory responses (e.g., by reducing matrix metalloproteinase expression) by bronchial epithelial cells ( 153 ), with potential benefits for epithelial barrier integrity ( 170 ). Vitamin D may promote the activity of T regulatory cells and reduce the potential for dendritic cells to activate and expand effector/pro-inflammatory T helper (Th) cell subsets including Th1 and Th17 cells ( 153 ).…”

“…Vitamin D may promote the activity of T regulatory cells and reduce the potential for dendritic cells to activate and expand effector/pro-inflammatory T helper (Th) cell subsets including Th1 and Th17 cells ( 153 ). Other postulated mechanisms of action include the capacity of vitamin D to regulate lung and gut microbiota, and inhibitory effects on fibrosis and aging (e.g., via Klotho-pathways) ( 170 ). Berthelot et al hypothesized that there may be benefits for 1,25(OH) 2 D for some manifestations of SARS-CoV-2 infection, including MIS-C and thrombic coagulopathy via downregulation of the STING (stimulator of interferon genes) pathway and production of IFNß ( 172 ).…”

Current Overview on Therapeutic Potential of Vitamin D in Inflammatory Lung Diseases

“…1,25(OH)2D inhibits angiogenesis by inhibiting the production of VEGF, which is reported to stimulate endothelial cell excitation, recruitment, and multiplication. In lung cancer cells treated with 1,25(OH)2D, parathyroid hormone-related protein (PTHrP), MMP-9, and MMP-2 expression and synthesis are similarly decreased [ 78 , 79 ]. Since PTHrP and MMPs are both important factors in carcinoma progression, this might be a major mechanism.…”

Vitamin D has an effect on airway inflammation and Th17/Treg balance in asthmatic mice

“…7 Vitamin D can radically alter and affect immune responses and inflammation. 8 Vitamin D by triggering excessive inflammatory response can manipulate various immunologic pathways in asthma. 9 Notably, vitamin D has the capacity to alleviate airway remodeling in asthma.…”