All-Trans Retinoic Acid-Triggered Antimicrobial Activity against Mycobacterium tuberculosis Is Dependent on NPC2
The Journal of Immunology (Impact Factor: 4.92). 02/2014; 192(5). DOI: 10.4049/jimmunol.1301686
A role for vitamin A in host defense against Mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the mechanism is unclear. In this study, we demonstrate that vitamin A-triggered antimicrobial activity against M. tuberculosis requires expression of NPC2. Comparison of monocytes stimulated with all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D3), the biologically active forms of vitamin A and vitamin D, respectively, indicates that ATRA and 1,25D3 induce mechanistically distinct antimicrobial activities. Stimulation of primary human monocytes with ATRA did not result in expression of the antimicrobial peptide cathelicidin, which is required for 1,25D3 antimicrobial activity. In contrast, ATRA triggered a reduction in the total cellular cholesterol concentration, whereas 1,25D3 did not. Blocking ATRA-induced cellular cholesterol reduction inhibits antimicrobial activity as well. Bioinformatic analysis of ATRA- and 1,25D3-induced gene profiles suggests that NPC2 is a key gene in ATRA-induced cholesterol regulation. Knockdown experiments demonstrate that ATRA-mediated decrease in total cellular cholesterol content and increase in lysosomal acidification are both dependent upon expression of NPC2. Expression of NPC2 was lower in caseous tuberculosis granulomas and M. tuberculosis-infected monocytes compared with normal lung and uninfected cells, respectively. Loss of NPC2 expression ablated ATRA-induced antimicrobial activity. Taken together, these results suggest that the vitamin A-mediated antimicrobial mechanism against M. tuberculosis requires NPC2-dependent expression and function, indicating a key role for cellular cholesterol regulation in the innate immune response.
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[Show abstract] [Hide abstract] ABSTRACT: Retinoic acid (RA), the active vitamin-A-metabolite, has well-established functions in skin homeostasis and in the immune system. Skin mast cells (MCs) combine traits of both structures, being of hematopoietic origin, but functional in the skin environment. It remains largely unknown whether mature MCs are targeted by the retinoid network. Here, we demonstrate that human skin MCs display substantial susceptibility to RA by which they are instructed to increase pro-inflammatory mediators (IL-1β, IL-8, TNF-α) but not histamine release. The effects are observed at physiological RA levels, in different microenvironments, and are largely donor-independent. RA susceptibility is owed to the cells' abundant expression of RARA, the receptor mediating MC cytokine responses. Unexpectedly, bioinformatics calculations on the FANTOM5 expression atlas revealed general enrichment of retinoid network components in MCs against other skin cells, and MCs rapidly upregulated RA responsive genes. In conclusion, MCs are important yet hitherto overlooked retinoid targets in the skin. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
- "In particular, RA was shown to act at critical checkpoints in the adaptive immune system, by regulating the differentiation and homing ability of CD4+ cells, especially of the regulatory T cell subset (Cassani et al., 2012; Hall et al., 2011; Mucida et al., 2007), and by stimulating B cell differentiation and isotype switching to IgA (Mora, 2008). In addition, RA was uncovered to modulate the function of myeloid immune cells including dendritic cells and macrophages, thereby aiding in combating diseases like tuberculosis (Geissmann et al., 2003; Manicassamy and Pulendran, 2009; Mohty et al., 2003; Tao et al., 2006; Wheelwright et al., 2014). An important resident immune cell subset of peripheral tissues is the mast cell (MC), which belongs to the myeloid arm of the hematopoietic system, but completes maturation only in direct contact with the target tissue after progenitor recruitment through the circulation . "
[Show abstract] [Hide abstract] ABSTRACT: Tuberculosis is continuing as a problem of mankind. With evolution, MDR and XDR forms of tuberculosis have emerged from drug sensitive strain. MDR and XDR strains are resistant to most of the antibiotics, making the management more difficult. BCG vaccine is not providing complete protection against tuberculosis. Therefore new infections are spreading at a tremendous rate. At the present moment there is experimental evidence to believe that Vitamin A and Vitamin D has anti-mycobacterial property. It is in this context, we have hypothesized a host based approach using the above vitamins that can cause possible prevention and cure of tuberculosis with minimal chance of resistance or toxicity.
- "Vitamin A and NPC2 appears to be linked since NPC2 expression is found to be less in caseous tuberculosis granuloma and its knockout cells are reported to be insensitive to Vitamin A therapy and do not show Vitamin A mediated antimicrobial action  . Unlike Vitamin D, Vitamin A has been reported not to alter the cathelicidin expression  . Similarly, Vitamin D increases the phagocytic activity of macrophages and further decreases the stability of phagosome via VDR–RXR heterodimer, allowing the phagosome–lysosome fusion. "
- [Show abstract] [Hide abstract] ABSTRACT: Tuberculosis is a leading cause of infectious disease-related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ- and IL-15-induced "defense response" genes. IL-32 induced the vitamin D-dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15-induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15-induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.