1,25-Dihydroxyvitamin D3 ameliorates neutrophilic asthma through modulation of ERS-NLRP3 inflammasome axis in a mouse model

Document Type : Original Article

Authors

1 Department of Clinical Research, The Wuming Affiliated Hospital of Guangxi Medical University, Nanning, China

2 Department of General Practice, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China

3 Department of Emergency, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China

10.22038/ijbms.2026.87901.19026

Abstract

Objective(s): Asthma is a heterogeneous disease. Neutrophilic asthma is associated with severe asthma and poor response to inhaled corticosteroids. We investigated whether 1,25-dihydroxyvitamin D3 can ameliorate neutrophilic airway inflammation, inhibit endoplasmic reticulum stress, and ERS-induced NLRP3 inflammasome activation in a murine model of neutrophilic asthma. 
Materials and Methods: BALB/c mice were established as an experimental model of neutrophilic asthma. 1,25-(OH)2D3 was administered for intervention to investigate the effect of Vitamin D3 on neutrophilic airway inflammation, ERS-induced NLRP3 activation. Inflammatory cells were counted in BALF, and lung tissue was histologically examined. Concentrations of IL-17, IL-1β, and IL-18 in BALF were measured. Immunohistochemical analysis of lung Ly-6G expression and AHR was tested. Furthermore, the percentage of Th17 cells was determined by flow cytometry. CHOP, GRP78, and NLRP3 protein expression was also examined by western blot. 
Results: We observed that the infiltration of inflammatory cells and goblet cell hyperplasia in lung and airway tissue were reduced by 1,25-(OH)2D3 treatment. The total number of inflammatory cells and the percentage of neutrophils in BALF were significantly less in the treatment groups. 1,25-(OH)2D3 obviously suppressed neutrophils infiltration and Ly-6G expression in neutrophilic asthma. 1,25-(OH)2D3 reduced Th17 cell percentage and IL-17 levels. The expression levels of GRP78 and CHOP were lower in the 1,25-(OH)2D3 treatment group than those in the NA model group. And, 1,25-(OH)2D3 decreased NLRP3 protein expression levels in the lungs of NA mice.
Conclusion: Our results suggest that 1,25-dihydroxyvitamin D3 ameliorates neutrophilic asthma in mice by a mechanism linked to reduced ERS and NLRP3 inflammasome activation, supporting further investigation of its potential as a therapeutic candidate.

Keywords

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References

1. Pelaia G, Vatrella A, Busceti MT, Gallelli L, Calabrese C, Terracciano R, et al. Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma. Mediators Inflamm 2015; 2015:879783.
2. Simpson JL, Phipps S, Baines KJ, Oreo KM, Gunawardhana L, Gibson PG. Elevated expression of the NLRP3 inflammasome in neutrophilic asthma. Eur Respir J 2014; 43:1067-1076.
3. Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, et al. Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma. Am J Respir Crit Care Med 2017; 196:283-297.
4. Li W, Cao T, Luo C, Cai J, Zhou X, Xiao X, et al. Crosstalk between ER stress, NLRP3 inflammasome, and inflammation. Appl Microbiol Biotechnol 2020; 104:6129-6140.
5. Pathinayake PS, Waters DW, Nichol KS, Brown AC, Reid AT, Hsu AC, et al. Endoplasmic reticulum-unfolded protein response signalling is altered in severe eosinophilic and neutrophilic asthma. Thorax 2022; 77:443-451.
6. Huang Y, Wang L, Jia XX, Lin XX, Zhang WX. Vitamin D alleviates airway remodeling in asthma by down-regulating the activity of Wnt/β-catenin signaling pathway. Int Immunopharmacol 2019; 68:88-94.
7. Agrawal T, Gupta GK, Agrawal DK. Vitamin D supplementation reduces airway hyperresponsiveness and allergic airway inflammation in a murine model. Clin Exp Allergy 2013; 43:672-683.
8. Jiang S, Zhang H, Li X, Yi B, Huang L, Hu Z, et al. Vitamin D/VDR attenuate cisplatin-induced AKI by down-regulating NLRP3/Caspase-1/GSDMD pyroptosis pathway. J Steroid Biochem Mol Biol 2021; 206:105789.
9. Yuan YF, Das SK, Li MQ. Vitamin D Ameliorates Impaired Wound Healing in Streptozotocin-Induced Diabetic Mice by Suppressing Endoplasmic Reticulum Stress. J Diabetes Res 2018; 2018:1757925.
10. Haas MJ, Jafri M, Wehmeier KR, Onstead-Haas LM, Mooradian AD. Inhibition of endoplasmic reticulum stress and oxidative stress by vitamin D in endothelial cells. Free Radic Biol Med 2016; 99:1-10.
11. Gao P, Tang K, Lu Y, Huang Z, Wang S, Wang M, et al. Pentraxin 3 promotes airway inflammation in experimental asthma. Respir Res 2020; 21:237.
12. Wang Y, Zhu J, Zhang L, Zhang Z, He L, Mou Y, et al. Role of C/EBP homologous protein and endoplasmic reticulum stress in asthma exacerbation by regulating the IL-4/signal transducer and activator of transcription 6/transcription factor EC/IL-4 receptor α positive feedback loop in M2 macrophages. J Allergy Clin Immunol 2017; 140:1550-1561 e1558.
13. Kim SR, Kim DI, Kang MR, Lee KS, Park SY, Jeong JS, et al. Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor κB activation. J Allergy Clin Immunol 2013; 132:1397-1408.
14. Hoffman SM, Tully JE, Nolin JD, Lahue KG, Goldman DH, Daphtary N, et al. Endoplasmic reticulum stress mediates house dust mite-induced airway epithelial apoptosis and fibrosis. Respir Res 2013; 14:141.
15. Chen X, Wang Y, Xie X, Chen H, Zhu Q, Ge Z, et al. Heme oxygenase-1 reduces sepsis-induced endoplasmic reticulum stress and acute lung injury. Mediators Inflamm 2018; 2018:9413876.
16. Fu T, Wang L, Zeng Q, Zhang Y, Sheng B, Han L. Ghrelin ameliorates asthma by inhibiting endoplasmic reticulum stress. Am J Med Sci 2017; 354:617-625.
17. Song JY, Fan B, Che L, Pan YR, Zhang SM, Wang Y, et al. Suppressing endoplasmic reticulum stress-related autophagy attenuates retinal light injury. Aging (Albany NY) 2020; 12:16579-16596.
18. Wang W, Liu T, Liu Y, Yu L, Yan X, Weng W, et al. Astaxanthin attenuates alcoholic cardiomyopathy via inhibition of endoplasmic reticulum stress-mediated cardiac apoptosis. Toxicol Appl Pharmacol 2021; 412:115378.
19. Li L, Zheng G, Cao C, Cao W, Yan H, Chen S, et al. The ameliorative effect of berberine on vascular calcification by inhibiting endoplasmic reticulum stress. J Cardiovasc Pharmacol 2022; 80:294-304.
20. Korn S, Hübner M, Jung M, Blettner M, Buhl R. Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency. Respir Res 2013; 14:25.
21. Taher YA, van Esch BC, Hofman GA, Henricks PA, van Oosterhout AJ. 1alpha,25-dihydroxyvitamin D3 potentiates the beneficial effects of allergen immunotherapy in a mouse model of allergic asthma: role for IL-10 and TGF-beta. J Immunol 2008; 180:5211-5221.
22. Zhou Y, Zhou X, Wang X. 1,25-Dihydroxyvitamin D3 prevented allergic asthma in a rat model by suppressing the expression of inducible nitric oxide synthase. Allergy Asthma Proc 2008; 29:258-267.
23. Cao R, Ma Y, Li S, Shen D, Yang S, Wang X, et al. 1,25(OH)(2) D(3) alleviates DSS-induced ulcerative colitis via inhibiting NLRP3 inflammasome activation. J Leukoc Biol 2020; 108:283-295.
24. Dong X, He Y, Ye F, Zhao Y, Cheng J, Xiao J, et al. Vitamin D3 ameliorates nitrogen mustard-induced cutaneous inflammation by inactivating the NLRP3 inflammasome through the SIRT3-SOD2-mtROS signaling pathway. Clin Transl Med 2021; 11:e312.
25. Li H, Zhong X, Li W, Wang Q. Effects of 1,25-dihydroxyvitamin D3 on experimental periodontitis and AhR/NF-κB/NLRP3 inflammasome pathway in a mouse model. J Appl Oral Sci 2019; 27:e20180713.
26. Wen G, Eder K, Ringseis R. 1,25-hydroxyvitamin D3 decreases endoplasmic reticulum stress-induced inflammatory response in mammary epithelial cells. PLoS One 2020; 15:e0228945.
27. Ramakrishnan RK, Al Heialy S, Hamid Q. Role of IL-17 in asthma pathogenesis and its implications for the clinic. Expert Rev Respir Med 2019; 13:1057-1068.
Iranian Journal of Basic Medical Sciences
Volume 29, Issue 3
March 2026
Pages 438-445

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