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Cathelicidin Mediates an Anti-Inflammatory Role of Active Vitamin D (Calcitriol) During M. paratuberculosis Infection

Vitamin D is a key regulator in calcium and phosphorus metabolism which are essential for maintaining bone health. Recent reports also showed a role for vitamin D in immune regulation which may be linked to vitamin D deficiency in autoimmune disorders including inflammatory diseases and Crohn’s dise...

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Autores principales: Vaccaro, Joseph A., Qasem, Ahmad, Naser, Saleh A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014016/
https://www.ncbi.nlm.nih.gov/pubmed/35444957
http://dx.doi.org/10.3389/fcimb.2022.875772
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author Vaccaro, Joseph A.
Qasem, Ahmad
Naser, Saleh A.
author_facet Vaccaro, Joseph A.
Qasem, Ahmad
Naser, Saleh A.
author_sort Vaccaro, Joseph A.
collection PubMed
description Vitamin D is a key regulator in calcium and phosphorus metabolism which are essential for maintaining bone health. Recent reports also showed a role for vitamin D in immune regulation which may be linked to vitamin D deficiency in autoimmune disorders including inflammatory diseases and Crohn’s disease (CD). This study examines the role of vitamin D deficiency in the regulation of Cathelicidin Antimicrobial Peptide (CAMP) in CD-like macrophages. The latter includes macrophages infected with Mycobacterium avium subsp. paratuberculosis (MAP) isolated from CD patient. Initially, we measured cathelicidin and calcitriol in ex vivo plasma samples from CD patients with or without MAP infection (N=40 per group). We also measured the expression and production of CAMP/LL-37, TNF-α, IL-1β, IL-10, cellular oxidative stress markers, and bacterial viability following treatment of MAP-infected macrophages with four different forms of vitamin D (D2, D3, calcifediol, and calcitriol). From these studies, we determined that LL-37 and calcitriol were significantly lower in CD samples from MAP-positive patients [155.55 ± 49.77 ng/mL and 51.48 ± 31.04 pg/mL, respectively] compared to MAP-negative patients [193.01 ± 78.95 ng/mL and 272.36 ± 94.77 pg/mL, respectively]. Moreover, calcitriol and calcifediol upregulated CAMP expression by nearly 5-fold and 3-fold, respectively. However, following MAP infection, only calcitriol increased CAMP by 3-folds. Both calcitriol and LL-37 reduced intracellular MAP viability by ~3 folds and inhibited TNF-α and IL-1β expression and production in these cells. Treating co-culture of Caco-2 monolayers and MAP-infected macrophages with LL-37 or calcitriol have shown a reduction in NOX-1 expression and DHE signal, in addition to a higher NADPH/NADPt ratio. Notably, calcitriol’s anti-inflammatory effects were lost upon CAMP knockdown by CAMP-siRNA transfection. Altogether, the data indicate that MAP infection and burden is significant in CD by disrupting the conversion of calcifediol to calcitriol and downregulation of CAMP expression leading to vitamin D deficiency.
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spelling pubmed-90140162022-04-19 Cathelicidin Mediates an Anti-Inflammatory Role of Active Vitamin D (Calcitriol) During M. paratuberculosis Infection Vaccaro, Joseph A. Qasem, Ahmad Naser, Saleh A. Front Cell Infect Microbiol Cellular and Infection Microbiology Vitamin D is a key regulator in calcium and phosphorus metabolism which are essential for maintaining bone health. Recent reports also showed a role for vitamin D in immune regulation which may be linked to vitamin D deficiency in autoimmune disorders including inflammatory diseases and Crohn’s disease (CD). This study examines the role of vitamin D deficiency in the regulation of Cathelicidin Antimicrobial Peptide (CAMP) in CD-like macrophages. The latter includes macrophages infected with Mycobacterium avium subsp. paratuberculosis (MAP) isolated from CD patient. Initially, we measured cathelicidin and calcitriol in ex vivo plasma samples from CD patients with or without MAP infection (N=40 per group). We also measured the expression and production of CAMP/LL-37, TNF-α, IL-1β, IL-10, cellular oxidative stress markers, and bacterial viability following treatment of MAP-infected macrophages with four different forms of vitamin D (D2, D3, calcifediol, and calcitriol). From these studies, we determined that LL-37 and calcitriol were significantly lower in CD samples from MAP-positive patients [155.55 ± 49.77 ng/mL and 51.48 ± 31.04 pg/mL, respectively] compared to MAP-negative patients [193.01 ± 78.95 ng/mL and 272.36 ± 94.77 pg/mL, respectively]. Moreover, calcitriol and calcifediol upregulated CAMP expression by nearly 5-fold and 3-fold, respectively. However, following MAP infection, only calcitriol increased CAMP by 3-folds. Both calcitriol and LL-37 reduced intracellular MAP viability by ~3 folds and inhibited TNF-α and IL-1β expression and production in these cells. Treating co-culture of Caco-2 monolayers and MAP-infected macrophages with LL-37 or calcitriol have shown a reduction in NOX-1 expression and DHE signal, in addition to a higher NADPH/NADPt ratio. Notably, calcitriol’s anti-inflammatory effects were lost upon CAMP knockdown by CAMP-siRNA transfection. Altogether, the data indicate that MAP infection and burden is significant in CD by disrupting the conversion of calcifediol to calcitriol and downregulation of CAMP expression leading to vitamin D deficiency. Frontiers Media S.A. 2022-04-04 /pmc/articles/PMC9014016/ /pubmed/35444957 http://dx.doi.org/10.3389/fcimb.2022.875772 Text en Copyright © 2022 Vaccaro, Qasem and Naser https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Vaccaro, Joseph A.
Qasem, Ahmad
Naser, Saleh A.
Cathelicidin Mediates an Anti-Inflammatory Role of Active Vitamin D (Calcitriol) During M. paratuberculosis Infection
title Cathelicidin Mediates an Anti-Inflammatory Role of Active Vitamin D (Calcitriol) During M. paratuberculosis Infection
title_full Cathelicidin Mediates an Anti-Inflammatory Role of Active Vitamin D (Calcitriol) During M. paratuberculosis Infection
title_fullStr Cathelicidin Mediates an Anti-Inflammatory Role of Active Vitamin D (Calcitriol) During M. paratuberculosis Infection
title_full_unstemmed Cathelicidin Mediates an Anti-Inflammatory Role of Active Vitamin D (Calcitriol) During M. paratuberculosis Infection
title_short Cathelicidin Mediates an Anti-Inflammatory Role of Active Vitamin D (Calcitriol) During M. paratuberculosis Infection
title_sort cathelicidin mediates an anti-inflammatory role of active vitamin d (calcitriol) during m. paratuberculosis infection
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014016/
https://www.ncbi.nlm.nih.gov/pubmed/35444957
http://dx.doi.org/10.3389/fcimb.2022.875772
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