Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis

Abstract

Epidemiological evidence correlates low serum vitamin A (retinol) levels with increased susceptibility to active tuberculosis (TB); however, retinol is biologically inactive and must be converted into its bioactive form, all-trans retinoic acid (ATRA). Given that ATRA triggers a Niemann-Pick type C2 (NPC2)-dependent antimicrobial response against Mycobacterium tuberculosis, we investigated the mechanism by which the immune system converts retinol into ATRA at the site of infection. We demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived dendritic cells (DCs), but not macrophages, express enzymes in the vitamin A metabolic pathway, including aldehyde dehydrogenase 1 family, member a2 (ALDH1A2) and short-chain dehydrogenase/reductase family, member 9 (DHRS9), enzymes capable of the two-step conversion of retinol into ATRA, which is subsequently released from the cell. Additionally, mRNA and protein expression levels of ALDH1A2 and DC marker CD1B were lower in tuberculosis lung tissues than in normal lung. The conditioned medium from DCs cultured with retinol stimulated antimicrobial activity from M. tuberculosis-infected macrophages, as well as the expression of NPC2 in monocytes, which was blocked by specific inhibitors, including retinoic acid receptor inhibitor (RARi) or N,N-diethylaminobenzaldehyde (DEAB), an ALDH1A2 inhibitor. These results indicate that metabolism of vitamin A by DCs transactivates macrophage antimicrobial responses. IMPORTANCE Tuberculosis (TB) is the leading cause of death by a single infectious agent worldwide. One factor that contributes to the success of the microbe is the deficiency in immunomodulatory nutrients, such as vitamin A (retinol), which are prevalent in areas where TB is endemic. Clinical trials show that restoration of systemic retinol levels in active TB patients is ineffective in mitigating the disease; however, laboratory studies demonstrate that activation of the vitamin A pathway in Mycobacterium tuberculosis-infected macrophages triggers an antimicrobial response. Therefore, the goal of this study was to determine the link between host retinol levels and retinoic acid-mediated antimicrobial responses against M. tuberculosis. By combining established in vitro models with in situ studies of lung tissue from TB patients, this study demonstrates that the innate immune system utilizes transcellular metabolism leading to activation between dendritic cells and macrophages as a means to combat the pathogen.

Comprehensive analysis of prognostic gene signatures based on immune infiltration of ovarian cancer

“…Dehydrogenase/family member 9 (DHRS9) is a member of the short chain dehydrogenase/ reductase family [62]. Studies have shown that DHRS9 is involved in the biosynthesis of all trans-retinoic acid and exerts an anti-tumour role by inhibiting the proliferation of tumour cells, including acute promyelocytic leukemia, squamous cell carcinoma, neurocytoma and hepatocellular carcinoma [63][64][65]. The formyl peptide receptor 1 (FPR1), a G-protein-coupled receptor expressed by bone marrow-derived cells [66], participates in activation of immune cell induced by N-formyl peptide [67,68].…”

Post-natal all-trans-retinoic acid biosynthesis

“…Immune cells express dhrs9, although reports disagree as to the specific cells involved. One report concluded that macrophages do not express dhrs9, whereas granulocyte-macrophage colonystimulating factor-derived dendritic cells do (Kim et al, 2019). Dendritic cells would secrete ATRA to resist pathogenesis in M. tuberculosis-infected macrophages.…”

“…The latter may explain frequent association of Raldh1 with cancer progression, not its ability to generate ATRA in some loci. In contrast, Raldh2 contributes to ATRA biosynthesis to trigger an antimicrobial response in tuberculosis: low expression of Raldh2 in lung characterizes the disease (Kim et al, 2019). ATRA has hormesis effects.…”

The role of vitamin A and vitamin D in the modulation of the immune response with focus on innate lymphoid cells

“…Although it is well known that nutritional deficiencies need to be diminished for the immune system to function adequately, recently emerged evidence suggest that increased intake of some nutrients, including vitamins, may help optimize the immune response and resistance to infection [6][7][8]. The impact of vitamin supplementation on the modulation of the immune response has always been in the focus of numerous studies [9][10][11][12]. We focused this review on vitamins A and D, since they were shown to have the greatest immunomodulatory impact.…”