Toll-like receptors in pathophysiology of asthma
https://doi.org/10.18093/0869-0189-2021-31-3-348-354
Abstract
In the last decade, significant research has been focused on Toll-like reseptors (TLRs) in the pathogenesis of respiratory diseases. The presented data show that TLR-mediated signaling can be directed both at the successful alleviation of the inflammatory reaction in the respiratory tract, and at its development and aggravation. Asthma is a chronic inflammatory disease of the respiratory tract caused by genetic factors, allergens, or microbial agents. TLRs play an important role in the pathogenesis of asthma. TLRs recognize a wide range of microbial molecules, endogenous molecules, and air allergens and modulate the allergic sensitization. An important feature of TLRs is their participation in the development of an immune response to viral and bacterial infections that cause severe exacerbations of asthma. TLRs are expressed on hematopoietic and non-hematopoietic airway cells, which play an immunomodulatory role in the development of asthma when activated by TLRs agonists. Due to the involvement of TLRs in innate and adaptive immunity and the ability to regulate adaptive Th-response, these receptors are currently being used as possible targets for drug development. Therefore, understanding the mechanisms and ways in which TLRs are involved in the pathogenesis of asthma may suggest new strategies for controlling the disease.
About the Authors
O. Yu. Kytikovа
Vladivostok Branch of Far Eastern Scientific Center of Physiology of Respiration – Research Institute of Medical Climatology and Rehabilitation Treatment
Russian Federation
Russian Federation
Oxana Yu. Kytikova, Doctor of Medicine, Researcher, Laboratory of Rehabilitation Treatment
ul. Russkaya 73G, Vladivostok, 690105
tel.: (423) 278-82-01
T. P. Novgorodtseva
Vladivostok Branch of Far Eastern Scientific Center of Physiology of Respiration – Research Institute of Medical Climatology and Rehabilitation Treatment
Russian Federation
Russian Federation
Tatyana P. Novgorodtseva, Doctor of Medicine, Professor, Deputy Director for science, Chief Researcher, Laboratory of Biomedical researches
ul. Russkaya 73G, Vladivostok, 690105
tel.: (423) 2788-202
Yu. K. Denisenko
Vladivostok Branch of Far Eastern Scientific Center of Physiology of Respiration – Research Institute of Medical Climatology and Rehabilitation Treatment
Russian Federation
Russian Federation
Yulia K. Denisenko, Doctor of Biology, Deputy Director for science, Head of the Laboratory of biomedical research
ul. Russkaya 73G, Vladivostok, 690105
tel.: (423) 278-82-01
M. V. Antonyuk
Vladivostok Branch of Far Eastern Scientific Center of Physiology of Respiration – Research Institute of Medical Climatology and Rehabilitation Treatment
Russian Federation
Russian Federation
Marina V. Antonyuk, Doctor of Medicine, Professor, Head of the Laboratory of rehabilitation treatment
ul. Russkaya 73G, Vladivostok, 690105
tel.: (423) 278-82-01
T. A. Gvozdenko
Vladivostok Branch of Far Eastern Scientific Center of Physiology of Respiration – Research Institute of Medical Climatology and Rehabilitation Treatment
Russian Federation
Russian Federation
Tatyana A. Gvozdenko, Doctor of Medicine, Professor of Russian Academy of Sciences, Chief Researcher, Laboratory of rehabilitation treatment
ul. Russkaya 73G, Vladivostok, 690105
tel.: (423) 278-82-01
References
1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated 2018. Available at: https://ginasthma.org/wp-content/uploads/2019/01/2018-GINA.pdf [Accessed: May 23, 2021].
2. Tsabouri S., Mavroudi A., Feketea G., Guibas G.V. Subcutaneous and sublingual immunotherapy in allergic asthma in children. Front. Pediatr. 2017; 5: 82. DOI: 10.3389/fped.2017.00082.
3. Wang Q., Imam M.U., Yida Z., Wang F. Peroxisome Proliferator-Activated Receptor gamma (PPARγ) as a target for concurrent management of diabetes and obesity-related cancer. Curr. Pharm. Des. 2017; 23 (25): 3677–3688. DOI: 10.2174/1381612823666170704125104.
4. Kytikova O.Yu., Gvozdenko T.A., Antonyuk M.V. [Modern aspects of prevalence of chronic bronchopulmonary diseases]. Byulleten’ fiziologii i patologii dykhaniya. 2017; (64): 94–100. Available at: https://cyberleninka.ru/article/n/sovremennye-aspekty-rasprostranennosti-hronicheskih-bronholegochnyh-zabolevaniy (in Russian).
5. Kytikova O. Yu., Antonyuk M.V., Gvozdenko T.A., Novgorodceva T.P. [Metabolic aspects of the relationship of asthma and obesity]. Ozhirenie i metabolizm. 2018; 15 (4): 9–14. DOI: 10.14341/omet9578 (in Russian).
6. Wenzel S. Severe asthma: from characteristics to phenotypes to endotypes. Clin. Exp. Allergy. 2012; 42 (5): 650–658. DOI: 10.1111/j.13652222.2011.03929.x.
7. Zakeri A., Russo M. Dual role of toll-like receptors in human and experimental asthma models. Front. Immunol. 2018; 9: 1027. DOI: 10.3389/fimmu.2018.01027.
8. Сhristou E.A.A., Giardino G., Stefanaki E., Ladomenou F. Asthma: An undermined state of immunodeficiency. Int. Rev. Immunol. 2019; 38 (2): 70–78. DOI: 10.1080/08830185.2019.1588267.
9. Lv J., Yu Q., Lv J. et al. Airway epithelial TSLP production of TLR2 drives type 2 immunity in allergic airway inflammation. Eur. J. Immunol. 2018; 48 (11): 1838–1850. DOI: 10.1002/eji.201847663.
10. Mirotti L., Alberca Custódio R.W., Gomes E. et al. CpG-ODN shapes alum adjuvant activity signaling via MyD88 and IL-10. Front. Immunol. 2017; 8: 47. DOI: 10.3389/fimmu.2017.00047.
11. De Nardo D. Toll-like receptors: activation, signalling and transcriptional modulation. Cytokine. 2015; 74 (2): 181–189. DOI: 10.1016/j.cyto.2015.02.025.
12. Shim J.U., Lee S.E., Hwang W. et al. Flagellin suppresses experimental asthma by generating regulatory dendritic cells and T cells. J. Allergy Clin. Immunol. 2016; 137 (2): 426–435. DOI: 10.1016/j.jaci.2015.07.010.
13. Suurmond J., Dorjée A.L., Knol E.F. et al. Differential TLR-induced cytokine production by human mast cells is amplified by FcεRI triggering. Clin. Exp. Allergy. 2015; 45 (4): 788–96. DOI: 10.1111/cea.12509.
14. Kvarnhammar A.M., Cardell L.O. Pattern-recognition receptors in human eosinophils. Immunology. 2012; 136 (1): 11–20. DOI: 10.1111/j.1365-2567.2012.03556.x.
15. Kim D.H., Choi E., Lee J.S. et al. House dust mite allergen regulates constitutive apoptosis of normal and asthmatic neutrophils via Tolllike receptor 4. PLoS One. 2015; 10 (5): e0125983. DOI: 10.1371/journal.pone.0125983.
16. Tan A.M., Chen H.C., Pochard P. et al. TLR4 signaling in stromal cells is critical for the initiation of allergic Th2 responses to inhaled antigen. J. Immunol. 2010; 184 (7): 3535–3544. DOI: 10.4049/jimmunol.0900340.
17. Tian B., Zhao Y., Sun H. et al. BRD4 mediates NF- κB-dependent epithelial-mesenchymal transition and pulmonary fibrosis via transcriptional elongation. Am. J. Physiol. Lung Cell. Mol. Physiol. 2016; 311 (6): L1183–1201. DOI: 10.1152/ajplung.00224.2016.
18. Bezemer G.F.G., Sagar S., van Bergenhenegouwen J. et al. Dual role of Toll-like receptors in asthma and chronic obstructive pulmonary disease. Pharmacol. Rev. 2012; 64 (2): 337–358. DOI: 10.1124/pr.111.004622.
19. Athari S.S., Athari S.M., Beyzay F. et al. Critical role of Toll-like receptors in pathophysiology of allergic asthma. Eur. J. Pharmacol. 2017; 808: 21–27. DOI: 10.1016/j.ejphar.2016.11.047.
20. Korppi M., Törmänen S. Toll-like receptor 1 and 10 variations increase asthma risk and review highlights further research directions. Acta Paediatr. 2019; 108 (8): 1406–1408. DOI: 10.1111/apa.14795.
21. Drexler S.K., Foxwell B.M. The role of Toll-like receptors in chronic inflammation. Int. J. Biochem. Cell Biol. 2010; 42 (4): 506–518. DOI: 10.1016/j.biocel.2009.10.009.
22. Yu Y., Yip K.H., Tam I.Y.S. et al. Differential effects of the Tolllike receptor 2 agonists, PGN and Pam3CSK4 on anti-IgE induced human mast cell activation. PLoSOne. 2014; 9 (11): e112989. DOI: 10.1371/journal.pone.0112989.
23. Yang D., Chen Q., Su S.B. et al. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. J. Exp. Med. 2008; 205 (1): 79–90. DOI: 10.1084/jem.20062027.
24. Ashour D.S. Toll-like receptor signaling in parasitic infections. Expert Rev. Clin. Immunol. 2015; 11 (6): 771–780. DOI: 10.1586/1744666X.2015.1037286.
25. Chen K., Xiang Y., Yao X. et al. The active contribution of Toll-like receptors to allergic airway inflammation. Int. Immunopharmacol. 2011; 11 (10): 1391–1398. DOI: 10.1016/j.intimp.2011.05.003.
26. Kearney S.C., Dziekiewicz M., Feleszko W. Immunoregulatory and immunostimulatory responses of bacterial lysates in respiratory infections and asthma. Ann. Allergy Asthma Immunol. 2015; 114 (5): 364–369. DOI: 10.1016/j.anai.2015.02.008.
27. Michels K.R., Lukacs N.W., Fonseca W. TLR activation and allergic disease: Early life microbiome and treatment. Curr. Allergy Asthma Rep. 2018; 18 (11): 61. DOI: 10.1007/s11882-018-0815-5.
28. Duthie M.S., Windish H.P., Fox C.B., Reed S.G. Use of defined TLR ligands as adjuvants within human vaccines. Immunol. Rev. 2011; 239 (1): 178–196. DOI: 10.1111/j.1600-065X.2010.00978.x.
29. Chun E., Lee S.H., Lee S.Y. et al. Toll-like receptor expression on peripheral blood mononuclear cells in asthmatics; implications for asthma management. J. Clin. Immunol. 2010; 30 (3): 459–464. DOI: 10.1007/s10875-009-9363-z.
30. Bruchard M., Rebé C., Derangère V. et al. The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. Nat. Immunol. 2015; 16 (8): 859–870. DOI: 10.1038/ni.3202.
31. Gong T., Yang Y., Jin T. et al. Orchestration of NLRP3 inflammasome activation by ion fluxes. Trends Immunol. 2018; 39 (5): 393–406. DOI: 10.1016/j.it.2018.01.009.
32. Patel B., Mann G.E., Chapple S.J. Concerted redox modulation by sulforaphane alleviates diabetes and cardiometabolic syndrome. Free Radic. Biol. Med. 2018; 122: 150–160. DOI: 10.1016/j.freeradbiomed.2018.02.004.
33. Nobs S.P., Natali S., Pohlmeier L. et al. PPARγ in dendritic cells and T cells drives pathogenic type-2 effector responses in lung inflammation. J. Exp. Med. 2017; 214 (10): 3015–3035. DOI: 10.1084/jem.20162069.
34. Koppenol-Raab M., Sjoelund V., Manes N.P. et al. Proteome and secretome analysis reveals differential post-transcriptional regulation of Toll-like receptor responses. Mol. Cell. Proteomics. 2017; 16 (4, Suppl. 1): S172–186. DOI: 10.1074/mcp.M116.064261.
35. Cheng Y., Li S., Wang M. et al. Peroxisome Proliferator Activated Receptor gamma (PPARγ) agonist rosiglitazone ameliorate airway inflammation by inhibiting Toll-like receptor 2 (TLR2)/Nod-like receptor with pyrin domain containing 3 (NLRP3) inflammatory corpuscle activation in asthmatic mice. Med. Sci. Monit. 2018; 24: 9045–9053. DOI: 10.12659/MSM.910766.
36. Fuchs B., Knothe S., Rochlitzer S. et al. A Toll-like receptor 2/6 agonist reduces allergic airway inflammation in chronic respiratory sensitisation to Timothy grass pollen antigens. Int. Arch. Allergy Immunol. 2010; 152 (2): 131–139. DOI: 10.1159/000265534.
37. Kormann M.S.D., Depner M., Hartl D. et al. Toll-like receptor heterodimer variants protect from childhood asthma. J. Allergy Clin. Immunol. 2008; 122 (1): 86–92. DOI: 10.1016/j.jaci.2008.04.039.
38. Eisenbarth S.C., Piggott D.A., Huleatt J.W. et al. Lipopolysaccharide-enhanced, Toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med. 2002; 196 (12): 1645–1651. DOI: 10.1084/jem.20021340.
39. Iwamura C., Nakayama T. Toll-like receptors in the respiratory system: their roles in inflammation. Curr. Allergy Asthma Rep. 2008; 8 (1): 7–13. DOI: 10.1007/s11882-008-0003-0.
40. Perros F., Lambrecht B.N., Hammad H. TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways. Respir. Res. 2011; 12 (1): 125. DOI: 10.1186/1465-9921-12-125.
41. Wang Y., McCusker C. Neonatal exposure with LPS and/or allergen prevents experimental allergic airways disease: Development of tolerance using environmental antigens. J. Allergy Clin. Immunol. 2006; 118 (1): 143–151. DOI: 10.1016/j.jaci.2006.03.020.
42. Zielen S., Trischler J., Schubert R. Lipopolysaccharide challenge: immunological effects and safety in humans. Expert Rev. Clin.Immunol. 2015; 11 (3): 409–418. DOI: 10.1586/1744666X.2015.1012158.
43. Schuijs M.J., Willart M.A., Vergote K. et al. Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells. Science. 2015; 349 (6252): 1106–1110. DOI: 10.1126/science.aac6623.
44. Millien V.O., Lu W., Shaw J. et al. Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science. 2013; 341 (6147): 792–796. DOI: 10.1126/science.1240342.
45. Herre J., Grönlund H., Brooks H. et al. Allergens as immunomodulatory proteins: The cat dander protein Fel d 1 enhances TLR activation by lipid ligands. J. Immunol. 2013; 191 (4): 1529–1535. DOI: 10.4049/jimmunol.1300284.
46. Denis O., Vincent M., Havaux X. et al. Induction of the specific allergic immune response is independent of proteases from the fungus Alternaria alternata. Eur. J. Immunol. 2013; 43 (4): 907–917. DOI: 10.1002/eji.201242630.
47. McSorley H.J., Blair N.F., Smith K.A. et al. Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy. Mucosal Immunol. 2014; 7 (5): 1068–1078. DOI: 10.1038/mi.2013.123.
48. Shikhagaie M.M., Andersson C.K., Mori M. et al. Mapping of TLR5 and TLR7 in central and distal human airways and identification of reduced TLR expression in severe asthma. Clin. Exp. Allergy. 2014; 44 (2): 184–196. DOI: 10.1111/cea.12176.
49. Lee B.L., Barton G.M. Trafficking of endosomal Toll-like receptors. Trends Cell Biol. 2014; 24 (6): 360–369. DOI: 10.1016/j.tcb.2013.12.002.
50. Torres D., Dieudonné A., Ryffel B. et al. Double-stranded RNA exacerbates pulmonary allergic reaction through TLR3: Implication of airway epithelium and dendritic cells. J. Immunol. 2010; 185 (1): 451–459. DOI: 10.4049/jimmunol.0902833.
51. Reuter S., Dehzad N., Martin H. et al. TLR3 but not TLR7/8 ligand induces allergic sensitization to inhaled allergen. J. Immunol. 2012; 188 (10): 5123–5131. DOI: 10.4049/jimmunol.1101618.
52. Hatchwell L., Collison A., Girkin J. et al. Toll-like receptor-7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia. Thorax. 2015; 70 (9): 854–861. DOI: 10.1136/thoraxjnl-2014-205465.
53. Lee L.M., Ji M., Sinha M. et al. Determinants of divergent adaptive immune responses after airway sensitization with ligands of Toll-like receptor 5 or Toll-like receptor 9. PLoS One. 2016; 11 (12): e0167693. DOI: 10.1371/journal.pone.0167693.
54. Drake M.G., Scott G.D., Proskocil B.J. et al. Toll-like receptor-7 rapidly relaxes human airways. Am. J. Respir. Crit. Care Med. 2013; 188 (6): 664–672. DOI: 10.1164/rccm.201303-0442OC.
55. Xu R.H., Wong E.B., Rubio D. et al. Sequential activation of two pathogen-sensing pathways required for type I interferon expression and resistance to an acute DNA virus infection. Immunity. 2015; 43 (6): 1148–1159. DOI: 10.1016/j.immuni.2015.11.015.
56. Jiao J., Wu J., Wang J. et al. Ma Huang Tang ameliorates bronchial asthma symptoms through the TLR9 pathway. Pharm. Biol. 2018; 56 (1): 580–593. DOI: 10.1080/13880209.2018.1517184.
57. Tworek D., Smith S.G., Salter B.M. et al. IL-25 receptor expression on airway dendritic cells after allergen challenge in subjects with asthma. Am. J. Respir. Crit. Care Med. 2016; 193 (9): 957–964. DOI: 10.1164/rccm.201509-1751OC.
58. Duechs M.J., Tilp C., Tomsic C. et al. Development of a novel severe triple allergen asthma model in mice which is resistant to dexamethasone and partially resistant to TLR7 and TLR9 agonist treatment. PLoS One. 2014; 9 (3): e91223. DOI: 10.1371/journal.pone.0091223.
59. Shan L., Hou P., Kang X., Shang Y. Effects of single-nucleotide polymorphisms in the TLR7 and TLR9 genes of asthmatic children. Ann. Clin. Lab. Sci. 2018; 48 (5): 601–607.
60. Vroman H., Bergen I.M., van Hulst J.A.C. et al. TNF-α-induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in eosinophilic or neutrophilic asthma. J. Allergy Clin. Immunol. 2018; 141 (5): 1620–1633. DOI: 10.1016/j.jaci.2017.08.012.
61. Рapaioannou A.I., Spathis A., Kostikas K. et al. The role of endosomal Toll-like receptors in asthma. Eur. J. Pharmacol. 2017; 808: 14–20. DOI: 10.1016/j.ejphar.2016.09.033.
Review
For citations:
Kytikovа O.Yu., Novgorodtseva T.P., Denisenko Yu.K., Antonyuk M.V., Gvozdenko T.A. Toll-like receptors in pathophysiology of asthma. PULMONOLOGIYA. 2021;31(3):348-354. (In Russ.) https://doi.org/10.18093/0869-0189-2021-31-3-348-354
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