Vitamin D3 promotes autophagy in THP‑1 cells infected with <em>Mycobacterium tuberculosis</em>

Wu,Yiming; Lin,Xue; Song,Fuyang; Xue,Di; Wang,Yujiong

doi:10.3892/etm.2022.11165

Vitamin D3 promotes autophagy in THP‑1 cells infected with Mycobacterium tuberculosis

Authors:
- Yiming Wu
- Xue Lin
- Fuyang Song
- Di Xue
- Yujiong Wang
View Affiliations

Affiliations: Key Laboratory of The Ministry of Education for Conservation and Utilization of Special Biological Resources in The West, Yinchuan, Ningxia 750021, P.R. China
Published online on: January 25, 2022 https://doi.org/10.3892/etm.2022.11165
Article Number: 240
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Tuberculosis (TB) is a major disease that causes mortality worldwide. The lethality of this disease is a result of the contagious bacteria Mycobacterium tuberculosis (M.tb). Infection can inhibit phagosomal maturation, with M.tb mainly attacking macrophages and inhibiting autophagy and apoptosis. Vitamin D has been used to treat tuberculosis, whereby the active metabolite, 1,25‑dihydroxyvitamin D, may enhance the immune response to M.tb. Moreover, macrophages infected with M.tb have a high demand for Ca²⁺. However, the mechanisms by which vitamin D3 protects against and treats TB remain unclear. In the present study, MTT assay showed that vitamin D3 decreased the viability of THP‑1 cells in a dose‑ and time‑dependent manner. Autophagy‑related factors in THP‑1 cells infected with M.tb were analyzed by western blotting and RT‑qPCR and the results demonstrated that vitamin D3 significantly increased the expression level of p62, LC3Ⅱ/LC3Ⅰ, Beclin‑1, ATG‑5 and AMPK in THP‑1 cells following M.tb infection. The Ca²⁺ concentration assay demonstrated that vitamin D3 may promoted cellular autophagy by inhibiting the concentration of Ca²⁺. Furthermore, the effect of vitamin D3 on M.tb infection was also assessed using Balb/c mice; pulmonary injury was assessed by H&E staining of the lungs tissue. The results demonstrated that vitamin D3 markedly attenuated cellular damage caused by M.tb infection. In conclusion, the present study indicated that vitamin D3 may activate cell autophagy signals by inhibiting the concentration of Ca²⁺. These data may improve understanding of the effect of vitamin D3 on M.tb infection and help determine the underlying mechanism of vitamin D3 to alleviate and treat the inflammatory response caused by TB.

View Figures

View References

1	Sharma S and Meena LS: Potential of Ca²⁺ in Mycobacterium tuberculosis H₃₇Rv pathogenesis and survival. Appl Biochem Biotechnol. 181:762–771. 2017.PubMed/NCBI View Article : Google Scholar
2	Chakaya JM, Harries AD and Marks GB: Ending tuberculosis by 2030-Pipe dream or reality? Int J Infect Dis. 92S:S51–S54. 2020.PubMed/NCBI View Article : Google Scholar
3	de Martino M, Lodi L, Galli L and Chiappini E: Immune response to Mycobacterium tuberculosis: A narrative review. Front Pediatr. 7(350)2019.PubMed/NCBI View Article : Google Scholar
4	Xu G, Wang J, Gao GF and Liu CH: Insights into battles between Mycobacterium tuberculosis and macrophages. Protein Cell. 5:728–736. 2014.PubMed/NCBI View Article : Google Scholar
5	Paik S and Jo EK: An interplay between autophagy and immunometabolism for host defense against mycobacterial infection. Front Immunol. 11(603951)2020.PubMed/NCBI View Article : Google Scholar
6	Monteith GR, Davis FM and Roberts-Thomson SJ: Calcium channels and pumps in cancer: Changes and consequences. J Biol Chem. 287:31666–31673. 2012.PubMed/NCBI View Article : Google Scholar
7	Huang W, Lu C, Wu Y, Ouyang S and Chen Y: T-type calcium channel antagonists, mibefradil and NNC-55-0396 inhibit cell proliferation and induce cell apoptosis in leukemia cell lines. J Exp Clin Cancer Res. 34(54)2015.PubMed/NCBI View Article : Google Scholar
8	Abu El Maaty MA and Wölfl S: Vitamin D as a novel regulator of tumor metabolism: Insights on potential mechanisms and implications for anti-cancer therapy. Int J Mol Sci. 18(3184)2017.PubMed/NCBI View Article : Google Scholar
9	Mondul AM, Weinstein SJ, Layne TM and Albanes D: Vitamin D and cancer risk and mortality: State of the science, gaps, and challenges. Epidemiol Rev. 39:28–48. 2017.PubMed/NCBI View Article : Google Scholar
10	Martineau AR: Old wine in new bottles: Vitamin D in the treatment and prevention of tuberculosis. Proc Nutr Soc. 71:84–89. 2012.PubMed/NCBI View Article : Google Scholar
11	Zhang L, Jiang X, Pfau D, Ling Y and Nathan CF: Type I interferon signaling mediates Mycobacterium tuberculosis-induced macrophage death. J Exp Med. 218(e20200887)2021.PubMed/NCBI View Article : Google Scholar
12	Rizzuto R, Pinton P, Ferrari D, Chami M, Szabadkai G, Magalhães PJ, Di Virgilio F and Pozzan T: Calcium and apoptosis: Facts and hypotheses. Oncogene. 22:8619–8627. 2003.PubMed/NCBI View Article : Google Scholar
13	Komohara Y, Fujiwara Y, Ohnishi K and Takeya M: Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev. 99:180–185. 2016.PubMed/NCBI View Article : Google Scholar
14	Chanput W, Mes J, Vreeburg RA, Savelkoul HF and Wichers HJ: Transcription profiles of LPS-stimulated THP-1 monocytes and macrophages: A tool to study inflammation modulating effects of food-derived compounds. Food Funct. 1:254–261. 2010.PubMed/NCBI View Article : Google Scholar
15	Kang P, Zhang W, Chen X, Yi X, Song P, Chang Y, Zhang S, Gao T, Li C and Li S: TRPM2 mediates mitochondria-dependent apoptosis of melanocytes under oxidative stress. Free Radic Biol Med. 126:259–268. 2018.PubMed/NCBI View Article : Google Scholar
16	Wang CH, Kao CH, Chen YF, Wei YH and Tsai TF: Cisd2 mediates lifespan: Is there an interconnection among Ca²⁺ homeostasis, autophagy, and lifespan? Free Radic Res. 48:1109–1114. 2014.PubMed/NCBI View Article : Google Scholar
17	Bussi C and Gutierrez MG: Mycobacterium tuberculosis infection of host cells in space and time. FEMS Microbiol Rev. 43:341–361. 2019.PubMed/NCBI View Article : Google Scholar
18	Adeniji AA, Knoll KE and Loots DT: Potential anti-TB investigational compounds and drugs with repurposing potential in TB therapy: A conspectus. Appl Microbiol Biotechnol. 104:5633–5662. 2020.PubMed/NCBI View Article : Google Scholar
19	Gough ME, Graviss EA and May EE: The dynamic immunomodulatory effects of vitamin D3 during Mycobacterium infection. Innate Immun. 23:506–523. 2017.PubMed/NCBI View Article : Google Scholar
20	Svensson D, Nebel D and Nilsson BO: Vitamin D3 modulates the innate immune response through regulation of the hCAP-18/LL-37 gene expression and cytokine production. Inflamm Res. 65:25–32. 2016.PubMed/NCBI View Article : Google Scholar
21	Riendeau CJ and Kornfeld H: THP-1 cell apoptosis in response to Mycobacterial infection. Infect Immun. 71:254–259. 2003.PubMed/NCBI View Article : Google Scholar
22	Chanput W, Mes JJ and Wichers HJ: THP-1 cell line: An in vitro cell model for immune modulation approach. Int Immunopharmacol. 23:37–45. 2014.PubMed/NCBI View Article : Google Scholar
23	Hashemipour S, Lalooha F, Zahir Mirdamadi S, Ziaee A and Dabaghi Ghaleh T: Effect of vitamin D administration in vitamin D-deficient pregnant women on maternal and neonatal serum calcium and vitamin D concentrations: A randomised clinical trial. Br J Nutr. 110:1611–1616. 2013.PubMed/NCBI View Article : Google Scholar
24	Luong KV and Nguyen LT: The beneficial role of vitamin D and its analogs in cancer treatment and prevention. Crit Rev Oncol Hematol. 73:192–201. 2010.PubMed/NCBI View Article : Google Scholar
25	Galati S, Boni C, Gerra MC, Lazzaretti M and Buschini A: Autophagy: A player in response to oxidative stress and DNA damage. Oxid Med Cell Longev. 2019(5692958)2019.PubMed/NCBI View Article : Google Scholar
26	Lamark T, Svenning S and Johansen T: Regulation of selective autophagy: The p62/SQSTM1 paradigm. Essays Biochem. 61:609–624. 2017.PubMed/NCBI View Article : Google Scholar
27	Zheng W, Xie W, Yin D, Luo R, Liu M and Guo F: ATG5 and ATG7 induced autophagy interplays with UPR via PERK signaling. Cell Commun Signal. 17(42)2019.PubMed/NCBI View Article : Google Scholar
28	He C and Levine B: The beclin 1 interactome. Curr Opin Cell Biol. 22:140–149. 2010.PubMed/NCBI View Article : Google Scholar
29	Song M, Bode AM, Dong Z and Lee MH: AKT as a therapeutic target for cancer. Cancer Res. 79:1019–1031. 2019.PubMed/NCBI View Article : Google Scholar
30	Revathidevi S and Munirajan AK: Akt in cancer: Mediator and more. Semin Cancer Biol. 59:80–91. 2019.PubMed/NCBI View Article : Google Scholar
31	Revathidevi S and Munirajan AK: An overview of autophagy: Morphology, mechanism, and regulation. Antioxid Redox Signal. 20:460–473. 2014.PubMed/NCBI View Article : Google Scholar
32	Kania E, Pająk B and Orzechowski A: Calcium homeostasis and ER stress in control of autophagy in cancer cells. Biomed Res Int. 2015(352794)2015.PubMed/NCBI View Article : Google Scholar
33	Pinton P, Giorgi C, Siviero R, Zecchini E and Rizzuto R: Calcium and apoptosis: ER-mitochondria Ca²⁺ transfer in the control of apoptosis. Oncogene. 27:6407–6418. 2008.PubMed/NCBI View Article : Google Scholar
34	Padhi A, Pattnaik K, Biswas M, Jagadeb M, Behera A and Sonawane A: Mycobacterium tuberculosis LprE suppresses TLR2-dependent cathelicidin and autophagy expression to enhance bacterial survival in macrophages. J Immunol. 203:2665–2678. 2019.PubMed/NCBI View Article : Google Scholar
35	El-Sharkawy A and Malki A: Vitamin D signaling in inflammation and cancer: Molecular mechanisms and therapeutic implications. Molecules. 25(3219)2020.PubMed/NCBI View Article : Google Scholar
36	Kimmey JM, Huynh JP, Weiss LA, Park S, Kambal A, Debnath J, Virgin HW and Stallings CL: Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature. 528:565–569. 2015.PubMed/NCBI View Article : Google Scholar