Luteolin Ameliorates Allergic Rhinitis in Mice through Modulating T Cell Subset Imbalance, Endoplasmic Reticulum Stress, and NLRP3 Inflammasome Axes
Abstract
Luteolin (LO) possesses pharmacological benefits like anti-inflammatory, antioxidant, and immune-boosting properties. This study aims to clarify the effect of LO on allergic rhinitis (AR) and its mechanisms and provide new insights for the clinical application of LO.
A mouse model for AR was developed through ovalbumin (OVA) stimulation. AR mice were gavaged with saline, low, medium, and high concentrations of LO, and montelukast. Nasal symptoms and scores were evaluated. The levels of OVA-specific immunoglobulins (OVA-sIgs), T helper cells (Th1, Th2, Th17), regulatory T cells (Tregs) cytokines, along with proinflammatory cytokines were measured using enzyme-linked immunosorbent assay (ELISA). Histopathological alterations were observed utilizing hematoxylin-eosin staining. Interleukin (IL)-1β and IL-18 levels were assessed through immunohistochemistry. Flow cytometry measured the percentage of T lymphocytes. The levels of endoplasmic reticulum stress (ERS)-related and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-related mRNAs and proteins were analyzed through reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.
LO reduced nasal symptom scores in AR mice, upregulated OVE-sIgG2a levels, and downregulated OVE-sIgE, OVE-sIgG1, and histamine levels. After the administration of LO, AR mice showed an increase in Th1 and Treg cytokines levels, while Th2 and Th17 cytokines levels were reduced. LO ameliorated the splenic T cell subset imbalance and attenuated inflammatory cell infiltration. LO reduced the levels of ERS-related and NLRP3 inflammasome activation-related mRNAs and proteins in the nasal mucosa.
LO ameliorated AR symptoms by regulating T cell subset imbalance, hindering ERS and NLRP3 inflammasome activation.
1. Siddiqui ZA, Walker A, Pirwani MM, Tahiri M, Syed I. Allergic rhinitis: diagnosis and management. Br J Hosp Med (Lond). 2022;83(2):1-9.
2. Wise SK, Damask C, Roland LT, Ebert C, Levy JM, Lin S, et al. International consensus statement on allergy and rhinology: Allergic rhinitis - 2023. Int Forum Allergy Rhinol. 2023;13(4):293-859.
3. McCarthy MW. Montelukast as a potential treatment for COVID-19. Expert Opin Pharmacother. 2023;24(5):551-5.
4. Mayoral K, Lizano-Barrantes C, Zamora V, Pont A, Miret C, Barrufet C, et al. Montelukast in paediatric asthma and allergic rhinitis: a systematic review and meta-analysis. Eur Respir Rev. 2023;32(170):230124.
5. Paljarvi T, Forton J, Luciano S, Herttua K, Fazel S. Analysis of Neuropsychiatric Diagnoses After Montelukast Initiation. JAMA network open. 2022;5(5):e2213643.
6. Lo CWH, Pathadka S, Qin SX, Fung LWY, Yan VKC, Yiu HHE, et al. Neuropsychiatric events associated with montelukast in patients with asthma: a systematic review. Eur Respir Rev. 2023;32(169):230079.
7. Shamji MH, Sharif H, Layhadi JA, Zhu R, Kishore U, Renz H. Diverse immune mechanisms of allergen immunotherapy for allergic rhinitis with and without asthma. J Allergy Clin Immunol. 2022;149(3):791-801.
8. Liu P, Kang C, Zhang J, Liu Y, Liu J, Hu T, et al. The role of dendritic cells in allergic diseases. Int Immunopharmacol. 2022;113(Pt B):109449.
9. Ai S, Lin Y, Zheng J, Zhuang X. Xingbi Gel Ameliorates Allergic Rhinitis by Regulating IFN-γ Gene Promoter Methylation in CD4+ T Cells via the ERK-DNMT Pathway. Frontiers in surgery. 2020;7:619053.
10. Ke X, Chen Z, Wang X, Kang H, Hong S. Quercetin improves the imbalance of Th1/Th2 cells and Treg/Th17 cells to attenuate allergic rhinitis. Autoimmunity. 2023;56(1):2189133.
11. Li J, Lin X, Liu X, Ma Z, Li Y. Baicalin regulates Treg/Th17 cell imbalance by inhibiting autophagy in allergic rhinitis. Mol Immunol. 2020;125:162-71.
12. Ren J, Bi Y, Sowers JR, Hetz C, Zhang Y. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases. Nat Rev Cardiol. 2021;18(7):499-521.
13. Chen X, Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer. 2021;21(2):71-88.
14. Liu JX, Zhen Z, Chen AN, Guo CL, Shi KT, Wang H, et al. Endoplasmic reticulum stress promotes local immunoglobulin E production in allergic rhinitis. Laryngoscope investigative otolaryngology. 2021;6(6):1256-66.
15. Resano A, Bhattacharjee S, Barajas M, Do KV, Aguado-Jiménez R, Rodríguez D, et al. Elovanoids Counteract Inflammatory Signaling, Autophagy, Endoplasmic Reticulum Stress, and Senescence Gene Programming in Human Nasal Epithelial Cells Exposed to Allergens. Pharmaceutics. 2022;14(1):113.
16. Fu J, Wu H. Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation. Annu Rev Immunol. 2023;41:301-16.
17. Xu J, Núñez G. The NLRP3 inflammasome: activation and regulation. Trends Biochem Sci. 2023;48(4):331-44.
18. Cheng N, Wang Y, Gu Z. Understanding the role of NLRP3-mediated pyroptosis in allergic rhinitis: A review. Biomed Pharmacother. 2023;165:115203.
19. Zhang W, Ba G, Tang R, Li M, Lin H. Ameliorative effect of selective NLRP3 inflammasome inhibitor MCC950 in an ovalbumin-induced allergic rhinitis murine model. Int Immunopharmacol. 2020;83:106394.
20. Hoang MP, Chitsuthipakorn W, Snidvongs K. Herbal Medicines for Allergic Rhinitis: a Systematic Review and Meta-analysis. Curr Allergy Asthma Rep. 2021;21(4):25.
21. Tesio AY, Robledo SN. Analytical determinations of luteolin. BioFactors. 2021;47(2):141-64.
22. Huang CY, Chen HW, Lo CW, Wang YR, Li CC, Liu KL, et al. Luteolin ameliorates palmitate-induced lipotoxicity in hepatocytes by mediating endoplasmic reticulum stress and autophagy. Food Chem Toxicol. 2023;171:113554.
23. Lee HJ, Seo HS, Ryu J, Yoon YP, Park SH, Lee CJ. Luteolin inhibited the gene expression, production and secretion of MUC5AC mucin via regulation of nuclear factor kappa B signaling pathway in human airway epithelial cells. Pulm Pharmacol Ther. 2015;31:117-22.
24. Chen Z, He S, Wei Y, Liu Y, Xu Q, Lin X, et al. Fecal and serum metabolomic signatures and gut microbiota characteristics of allergic rhinitis mice model. Front Cell Infect Microbiol. 2023;13:1150043.
25. Gao Z, Lv H, Wang Y, Xie Y, Guan M, Xu Y. TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice. Mol Med. 2023;29(1):160.
26. Senturk E, Yildirim YS, Dogan R, Ozturan O, Guler EM, Aydin MS, et al. Assessment of the effectiveness of cyclosporine nasal spray in an animal model of allergic rhinitis. Eur Arch Otorhinolaryngol. 2018;275(1):117-24.
27. Xi GP, Zhang Q, Yin J. Establishment and characterization of murine models of asthma and subcutaneous immunotherapy for Humulus pollen allergy. Immun Inflamm Disease. 2021;9(2):443-55.
28. Zhang JJ, He XC, Zhou M, Liu QD, Xu WZ, Yan YJ, et al. Xiao-qing-long-tang ameliorates OVA-induced allergic rhinitis by inhibiting ILC2s through the IL-33/ST2 and JAK/STAT pathways. Phytomedicine. 2023;119:155012.
29. Drazdauskaitė G, Layhadi JA, Shamji MH. Mechanisms of Allergen Immunotherapy in Allergic Rhinitis. Curr Allergy Asthma Rep. 2020;21(1):2.
30. Zhang Y, Lan F, Zhang L. Update on pathomechanisms and treatments in allergic rhinitis. Allergy. 2022;77(11):3309-19.
31. Correia da Silva D, Valentão P, Pereira DM. Naturally occurring small molecules with dual effect upon inflammatory signaling pathways and endoplasmic reticulum stress response. J Physiol Biochem. 2024;80(2):421-37.
32. Jang TY, Jung AY, Kyung TS, Kim DY, Hwang JH, Kim YH. Anti-allergic effect of luteolin in mice with allergic asthma and rhinitis. Central-Europ J Immunol. 2017;42(1):24-9.
33. Qiao XR, Feng T, Zhang D, Zhi LL, Zhang JT, Liu XF, et al. Luteolin alleviated neutrophilic asthma by inhibiting IL-36γ secretion-mediated MAPK pathways. Pharm Biol. 2023;61(1):165-76.
34. Eguiluz-Gracia I, Layhadi JA, Rondon C, Shamji MH. Mucosal IgE immune responses in respiratory diseases. Curr Opin Pharmacol. 2019;46:100-7.
35. Bruni FM, Coutinho EMM, Andrade-Barros AI, Grund LZ, Lopes-Ferreira M, Lima C. Anaphylaxis induced by Thalassophryne nattereri venom in mice is an IgE/IgG1-mediated, IL-4-dependent phenomenon. Sci Rep. 2020;10(1):584.
36. Lei H, Sun Y, Quan S. IL-37 relieves allergic inflammation by inhibiting the CCL11 signaling pathway in a mouse model of allergic rhinitis. Exp Ther Med. 2020;20(4):3114-21.
37. Fan Y, Yang C, Zhou J, Cheng X, Dong Y, Wang Q, et al. Regulatory effect of glutathione on treg/Th17 cell balance in allergic rhinitis patients through inhibiting intracellular autophagy. Immunopharmacol Immunotoxicol. 2021;43(1):58-67.
38. Zhu Y, Yu J, Zhu X, Yuan J, Dai M, Bao Y, et al. Experimental observation of the effect of immunotherapy on CD4+ T cells and Th1/Th2 cytokines in mice with allergic rhinitis. Sci Rep. 2023;13(1):5273.
39. You X, Sun X, Kong J, Tian J, Shi Y, Li X. D-Pinitol Attenuated Ovalbumin-induced Allergic Rhinitis in Experimental Mice via Balancing Th1/Th2 Response. Iran J Allergy Asthma Immunol. 2021;20(6):672-83.
40. Duan Q, Zhou Y, Yang D. Endoplasmic reticulum stress in airway hyperresponsiveness. Biomed Pharmacother. 2022;149:112904.
41. Lv XF, Wen RQ, Liu K, Zhao XK, Pan CL, Gao X, et al. Role and molecular mechanism of traditional Chinese medicine in preventing cardiotoxicity associated with chemoradiotherapy. Front Cardiovasc Med. 2022;9:1047700.
42. Kou JJ, Shi JZ, He YY, Hao JJ, Zhang HY, Luo DM, et al. Luteolin alleviates cognitive impairment in Alzheimer's disease mouse model via inhibiting endoplasmic reticulum stress-dependent neuroinflammation. Acta Pharmacol Sin. 2022;43(4):840-9.
43. Zhou H, Zhang W, Qin D, Liu P, Fan W, Lv H, et al. Activation of NLRP3 inflammasome contributes to the inflammatory response to allergic rhinitis via macrophage pyroptosis. Int Immunopharmacol. 2022;110:109012.
44. Yang Z, Liang C, Wang T, Zou Q, Zhou M, Cheng Y, et al. NLRP3 inflammasome activation promotes the development of allergic rhinitis via epithelium pyroptosis. Biochem Biophys Res Commun. 2020;522(1):61-7.
45. Gong G, Huang P, Yang C, Huang C, Zhang Z, Chen R, et al. Effects of Blocking NLRP3 Inflammasome on Type II Innate Lymphoid Cell Response in Allergic Rhinitis. Iran J Immunol. 2023;3(20):287-302.
46. Liu Z, Gao S, Bu Y, Zheng X. Luteolin Protects Cardiomyocytes Cells against Lipopolysaccharide-Induced Apoptosis and Inflammatory Damage by Modulating Nlrp3. Yonsei Med J. 2022;63(3):220-8.
2. Wise SK, Damask C, Roland LT, Ebert C, Levy JM, Lin S, et al. International consensus statement on allergy and rhinology: Allergic rhinitis - 2023. Int Forum Allergy Rhinol. 2023;13(4):293-859.
3. McCarthy MW. Montelukast as a potential treatment for COVID-19. Expert Opin Pharmacother. 2023;24(5):551-5.
4. Mayoral K, Lizano-Barrantes C, Zamora V, Pont A, Miret C, Barrufet C, et al. Montelukast in paediatric asthma and allergic rhinitis: a systematic review and meta-analysis. Eur Respir Rev. 2023;32(170):230124.
5. Paljarvi T, Forton J, Luciano S, Herttua K, Fazel S. Analysis of Neuropsychiatric Diagnoses After Montelukast Initiation. JAMA network open. 2022;5(5):e2213643.
6. Lo CWH, Pathadka S, Qin SX, Fung LWY, Yan VKC, Yiu HHE, et al. Neuropsychiatric events associated with montelukast in patients with asthma: a systematic review. Eur Respir Rev. 2023;32(169):230079.
7. Shamji MH, Sharif H, Layhadi JA, Zhu R, Kishore U, Renz H. Diverse immune mechanisms of allergen immunotherapy for allergic rhinitis with and without asthma. J Allergy Clin Immunol. 2022;149(3):791-801.
8. Liu P, Kang C, Zhang J, Liu Y, Liu J, Hu T, et al. The role of dendritic cells in allergic diseases. Int Immunopharmacol. 2022;113(Pt B):109449.
9. Ai S, Lin Y, Zheng J, Zhuang X. Xingbi Gel Ameliorates Allergic Rhinitis by Regulating IFN-γ Gene Promoter Methylation in CD4+ T Cells via the ERK-DNMT Pathway. Frontiers in surgery. 2020;7:619053.
10. Ke X, Chen Z, Wang X, Kang H, Hong S. Quercetin improves the imbalance of Th1/Th2 cells and Treg/Th17 cells to attenuate allergic rhinitis. Autoimmunity. 2023;56(1):2189133.
11. Li J, Lin X, Liu X, Ma Z, Li Y. Baicalin regulates Treg/Th17 cell imbalance by inhibiting autophagy in allergic rhinitis. Mol Immunol. 2020;125:162-71.
12. Ren J, Bi Y, Sowers JR, Hetz C, Zhang Y. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases. Nat Rev Cardiol. 2021;18(7):499-521.
13. Chen X, Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer. 2021;21(2):71-88.
14. Liu JX, Zhen Z, Chen AN, Guo CL, Shi KT, Wang H, et al. Endoplasmic reticulum stress promotes local immunoglobulin E production in allergic rhinitis. Laryngoscope investigative otolaryngology. 2021;6(6):1256-66.
15. Resano A, Bhattacharjee S, Barajas M, Do KV, Aguado-Jiménez R, Rodríguez D, et al. Elovanoids Counteract Inflammatory Signaling, Autophagy, Endoplasmic Reticulum Stress, and Senescence Gene Programming in Human Nasal Epithelial Cells Exposed to Allergens. Pharmaceutics. 2022;14(1):113.
16. Fu J, Wu H. Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation. Annu Rev Immunol. 2023;41:301-16.
17. Xu J, Núñez G. The NLRP3 inflammasome: activation and regulation. Trends Biochem Sci. 2023;48(4):331-44.
18. Cheng N, Wang Y, Gu Z. Understanding the role of NLRP3-mediated pyroptosis in allergic rhinitis: A review. Biomed Pharmacother. 2023;165:115203.
19. Zhang W, Ba G, Tang R, Li M, Lin H. Ameliorative effect of selective NLRP3 inflammasome inhibitor MCC950 in an ovalbumin-induced allergic rhinitis murine model. Int Immunopharmacol. 2020;83:106394.
20. Hoang MP, Chitsuthipakorn W, Snidvongs K. Herbal Medicines for Allergic Rhinitis: a Systematic Review and Meta-analysis. Curr Allergy Asthma Rep. 2021;21(4):25.
21. Tesio AY, Robledo SN. Analytical determinations of luteolin. BioFactors. 2021;47(2):141-64.
22. Huang CY, Chen HW, Lo CW, Wang YR, Li CC, Liu KL, et al. Luteolin ameliorates palmitate-induced lipotoxicity in hepatocytes by mediating endoplasmic reticulum stress and autophagy. Food Chem Toxicol. 2023;171:113554.
23. Lee HJ, Seo HS, Ryu J, Yoon YP, Park SH, Lee CJ. Luteolin inhibited the gene expression, production and secretion of MUC5AC mucin via regulation of nuclear factor kappa B signaling pathway in human airway epithelial cells. Pulm Pharmacol Ther. 2015;31:117-22.
24. Chen Z, He S, Wei Y, Liu Y, Xu Q, Lin X, et al. Fecal and serum metabolomic signatures and gut microbiota characteristics of allergic rhinitis mice model. Front Cell Infect Microbiol. 2023;13:1150043.
25. Gao Z, Lv H, Wang Y, Xie Y, Guan M, Xu Y. TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1β pathway in microglia of allergic rhinitis mice. Mol Med. 2023;29(1):160.
26. Senturk E, Yildirim YS, Dogan R, Ozturan O, Guler EM, Aydin MS, et al. Assessment of the effectiveness of cyclosporine nasal spray in an animal model of allergic rhinitis. Eur Arch Otorhinolaryngol. 2018;275(1):117-24.
27. Xi GP, Zhang Q, Yin J. Establishment and characterization of murine models of asthma and subcutaneous immunotherapy for Humulus pollen allergy. Immun Inflamm Disease. 2021;9(2):443-55.
28. Zhang JJ, He XC, Zhou M, Liu QD, Xu WZ, Yan YJ, et al. Xiao-qing-long-tang ameliorates OVA-induced allergic rhinitis by inhibiting ILC2s through the IL-33/ST2 and JAK/STAT pathways. Phytomedicine. 2023;119:155012.
29. Drazdauskaitė G, Layhadi JA, Shamji MH. Mechanisms of Allergen Immunotherapy in Allergic Rhinitis. Curr Allergy Asthma Rep. 2020;21(1):2.
30. Zhang Y, Lan F, Zhang L. Update on pathomechanisms and treatments in allergic rhinitis. Allergy. 2022;77(11):3309-19.
31. Correia da Silva D, Valentão P, Pereira DM. Naturally occurring small molecules with dual effect upon inflammatory signaling pathways and endoplasmic reticulum stress response. J Physiol Biochem. 2024;80(2):421-37.
32. Jang TY, Jung AY, Kyung TS, Kim DY, Hwang JH, Kim YH. Anti-allergic effect of luteolin in mice with allergic asthma and rhinitis. Central-Europ J Immunol. 2017;42(1):24-9.
33. Qiao XR, Feng T, Zhang D, Zhi LL, Zhang JT, Liu XF, et al. Luteolin alleviated neutrophilic asthma by inhibiting IL-36γ secretion-mediated MAPK pathways. Pharm Biol. 2023;61(1):165-76.
34. Eguiluz-Gracia I, Layhadi JA, Rondon C, Shamji MH. Mucosal IgE immune responses in respiratory diseases. Curr Opin Pharmacol. 2019;46:100-7.
35. Bruni FM, Coutinho EMM, Andrade-Barros AI, Grund LZ, Lopes-Ferreira M, Lima C. Anaphylaxis induced by Thalassophryne nattereri venom in mice is an IgE/IgG1-mediated, IL-4-dependent phenomenon. Sci Rep. 2020;10(1):584.
36. Lei H, Sun Y, Quan S. IL-37 relieves allergic inflammation by inhibiting the CCL11 signaling pathway in a mouse model of allergic rhinitis. Exp Ther Med. 2020;20(4):3114-21.
37. Fan Y, Yang C, Zhou J, Cheng X, Dong Y, Wang Q, et al. Regulatory effect of glutathione on treg/Th17 cell balance in allergic rhinitis patients through inhibiting intracellular autophagy. Immunopharmacol Immunotoxicol. 2021;43(1):58-67.
38. Zhu Y, Yu J, Zhu X, Yuan J, Dai M, Bao Y, et al. Experimental observation of the effect of immunotherapy on CD4+ T cells and Th1/Th2 cytokines in mice with allergic rhinitis. Sci Rep. 2023;13(1):5273.
39. You X, Sun X, Kong J, Tian J, Shi Y, Li X. D-Pinitol Attenuated Ovalbumin-induced Allergic Rhinitis in Experimental Mice via Balancing Th1/Th2 Response. Iran J Allergy Asthma Immunol. 2021;20(6):672-83.
40. Duan Q, Zhou Y, Yang D. Endoplasmic reticulum stress in airway hyperresponsiveness. Biomed Pharmacother. 2022;149:112904.
41. Lv XF, Wen RQ, Liu K, Zhao XK, Pan CL, Gao X, et al. Role and molecular mechanism of traditional Chinese medicine in preventing cardiotoxicity associated with chemoradiotherapy. Front Cardiovasc Med. 2022;9:1047700.
42. Kou JJ, Shi JZ, He YY, Hao JJ, Zhang HY, Luo DM, et al. Luteolin alleviates cognitive impairment in Alzheimer's disease mouse model via inhibiting endoplasmic reticulum stress-dependent neuroinflammation. Acta Pharmacol Sin. 2022;43(4):840-9.
43. Zhou H, Zhang W, Qin D, Liu P, Fan W, Lv H, et al. Activation of NLRP3 inflammasome contributes to the inflammatory response to allergic rhinitis via macrophage pyroptosis. Int Immunopharmacol. 2022;110:109012.
44. Yang Z, Liang C, Wang T, Zou Q, Zhou M, Cheng Y, et al. NLRP3 inflammasome activation promotes the development of allergic rhinitis via epithelium pyroptosis. Biochem Biophys Res Commun. 2020;522(1):61-7.
45. Gong G, Huang P, Yang C, Huang C, Zhang Z, Chen R, et al. Effects of Blocking NLRP3 Inflammasome on Type II Innate Lymphoid Cell Response in Allergic Rhinitis. Iran J Immunol. 2023;3(20):287-302.
46. Liu Z, Gao S, Bu Y, Zheng X. Luteolin Protects Cardiomyocytes Cells against Lipopolysaccharide-Induced Apoptosis and Inflammatory Damage by Modulating Nlrp3. Yonsei Med J. 2022;63(3):220-8.
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| Keywords | ||
| Allergic rhinitis Endoplasmic reticulum stress Luteolin NOD-like receptor family pyrin domain containing 3 inflammasome | ||
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How to Cite
1.
Guo X, Liu Y, Chen X. Luteolin Ameliorates Allergic Rhinitis in Mice through Modulating T Cell Subset Imbalance, Endoplasmic Reticulum Stress, and NLRP3 Inflammasome Axes. Iran J Allergy Asthma Immunol. 2025;:1-14.
