A novel 1,25-dihydroxyvitamin D–activin A pathway in human alveolar macrophages is dysfunctional in patients with pulmonary alveolar proteinosis (PAP)

Abstract

We have shown that activin A, a cytokine implicated in regulating B-cell proliferation, is severely deficient in alveolar macrophages from patients with pulmonary alveolar proteinosis (PAP), an autoimmune disorder characterized by surfactant accumulation and neutralizing autoantibodies to granulocyte-macrophage colony stimulating factor. Mechanisms of activin regulation in alveolar macrophages are not well understood. Based on previous gene array results from PAP bronchoalveolar lavage cells suggesting deficiencies in vitamin D target genes, and on recent evidence of vitamin D receptor elements (VDREs) in the human activin A gene promoter, we investigated the effects of 1,25-dihydroxyvitamin D (vitamin D(3)) on activin A expression in alveolar macrophages from healthy individuals and PAP patients. Activin A expression was stimulated by LPS in cultures of either healthy control or PAP alveolar macrophages; in contrast, vitamin D(3) increased activin A only in healthy controls but not in PAP. Compared to healthy controls, freshly obtained (uncultured) PAP alveolar macrophages displayed healthy intrinsic vitamin D receptor expression but deficient expression of vitamin D target genes, cathelicidin and thioredoxin interacting protein. PAP patients also demonstrated a relative insufficiency of circulating vitamin D. Investigation of activin A in murine alveolar macrophages confirmed a lack of functional response to vitamin D as anticipated since murine activin A does not contain VDREs. Results suggest that mechanisms of activin A deficiency in PAP alveolar macrophages may involve dysregulation of a novel species-specific vitamin D-activin A pathway.

1α,25‐dihydroxyvitamin D3 stimulates activin A production to fine‐tune osteoblast‐induced mineralization

“…A possible direct interaction between 1,25D3 and activin A is implicated by in silico analyses showing potential VDREs in the promoter of the human genes encoding activin A ( INHBA ) and the activin A receptor ( ACVR1B )(Wang et al, ). Albeit that the functionality of those VDREs was not validated, the observation of 1,25D3‐induced activin A production in human alveolar macrophages (Barna et al, ) and in human osteoblasts (this study) supports the presence of functional VDREs. Furthermore, we show that the shift in the activin A/FST ratio by 1,25D3 in human osteoblasts resulted in elevated activin signaling.…”

GM-CSF pathway correction in pulmonary alveolar proteinosis

“…Activin A, a cytokine regulating B-cell proliferation, was also found to be deficient in alveolar macrophages from patients with idiopathic pulmonary alveolar proteinosis (PAP), and this was found to be related to a defective 1,25-dihydroxyvitamin D (vitamin D3) pathway, due to lower serum levels of D3 vitamin and reduced expression of vitamin D target genes, cathelicidin and thioredoxin-interacting protein [42].…”

Rays of immunity: Role of sunshine vitamin in management of COVID-19 infection and associated comorbidities

“…Vitamin D has demonstrated regulatory effects on matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMP) inhibitors these are secreted from the cells and promote cellular remodelling and repair [71]. Activin A was upregulated in human alveolar macrophages after cultured with calcitriol for 24 h [72]. Vitamin D enhances cellular repair and cell proliferation in alveolar epithelial type II cells in lungs and inhibits primary cell apoptosis of AT II cells.…”