Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation

Abstract

Deficiency of vitamin D is associated with accelerated decline in lung function. Vitamin D is a ligand for nuclear hormone vitamin D receptor (VDR), and upon binding it modulates various cellular functions. The level of VDR is reduced in lungs of patients with chronic obstructive pulmonary disease (COPD) which led us to hypothesize that deficiency of VDR leads to significant alterations in lung phenotype that are characteristics of COPD/emphysema associated with increased inflammatory response. We found that VDR knock-out (VDR^–/–) mice had increased influx of inflammatory cells, phospho-acetylation of nuclear factor-kappaB (NF-κB) associated with increased proinflammatory mediators, and up-regulation of matrix metalloproteinases (MMPs) MMP-2, MMP-9, and MMP-12 in the lung. This was associated with emphysema and decline in lung function associated with lymphoid aggregates formation compared to WT mice. These findings suggest that deficiency of VDR in mouse lung can lead to an early onset of emphysema/COPD because of chronic inflammation, immune dysregulation, and lung destruction.

Introduction

Vitamin D deficiency has become an important global public-health problem with an estimate of more than 1 billion people worldwide having low/insufficient serum levels of vitamin D [1], [2], [3], [4]. Vitamin D deficiency is linked to decline in lung function, reduced immunity, and increased inflammation [4], [5], [6], [7], [8], [9]. Hence, studies to understand the role of vitamin D in pathogenesis of lung diseases with respect to vitamin D, vitamin D receptor (VDR) and vitamin D-binding protein are considerable interests [6].

Vitamin D belongs to a steroid hormone superfamily of nuclear receptors that has pleotropic protective effects on several diseases and disorders including asthma and chronic obstructive pulmonary disease (COPD) [4], [7], [8]. 1,25(OH)₂D₃ (1,25-dihydroxyvitamin D₃) an active metabolite of vitamin D (which binds to nuclear receptor VDR and interacts with other steroid hormone receptors), is a potent regulator of the immune response in Th1 cell-directed diseases [10], [11]. Ligand binding activates VDR, which forms a heterodimer with its partner, the retinoid X receptor (RXR), and this complex VDR/RXR further binds to specific genomic sequences in the promoter region of target genes (vitamin D response elements) and thus recruit transcription factors and co-regulatory molecules to activate or suppress gene transcription [12], [13].

Vitamin D and VDR are important regulators of inflammation in the lungs. Recent epidemiological studies showed a significant correlation between low serum concentrations of 25-hydroxy vitamin D and chronic lung diseases, such as asthma [14] and COPD [4], and accelerated decline in lung function [2], [7]. However, the molecular mechanisms underlying these phenomena are not known. It may be possible that vitamin D or VDR deficiency would invoke lung inflammation and alteration in lung function by proteinase/antiproteinase imbalance. Lung levels of VDR protein is decreased in patients with COPD which led us to hypothesize that VDR deficiency in mouse (VDR^–/– mice) can lead to abnormal lung phenotype, due to differential modulation of signaling mediators, and immune dysfunction further leading to spontaneous airspace enlargement and altered lung function. We tested the hypothesis by studying the lung inflammatory cellular influx, posttranslational modifications (phosphorylation and acetylation) of NF-κB RelA/p65, levels of proinflammatory mediators, levels/activities of extracellular matrix proteins, mean airspace enlargement, lymphoid aggregates formation and pulmonary function in lungs of VDR^–/– mice.