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Role of Toll-Like Receptors in Molecular and Cellular Mechanisms of Respiratory Diseases

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Targeting Cellular Signalling Pathways in Lung Diseases

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Abstract

The family of toll-like receptors (TLRs) is receiving considerable attention as potential regulators and controllers of the immune response through their ability to recognize and defend against invading pathogens. TLRs are key components of the innate immune system. Inappropriate or unregulated activation of TLR signaling can lead to chronic inflammation and autoimmune disorders. TLRs have been implicated in a number of lung-associated immune responses and pathogenesis of some respiratory diseases including asthma, chronic obstructive pulmonary disease, lung cancer, and infections. This chapter details the different TLRs, signaling transduction of TLR, defines their possible role in the pathogenesis of the main respiratory diseases, and finally, speculates over the therapeutic possibilities by targeting TLR signaling.

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References

  1. Crespo-Lessmann A, Juárez-Rubio C, Plaza-Moral V (2010) Role of toll-like receptors in respiratory diseases. Arch Bronconeumol 46(3):135–142

    Article  PubMed  PubMed Central  Google Scholar 

  2. Duez C, Gosset P, Tonnel A-B (2006) Dendritic cells and toll-like receptors in allergy and asthma. Eur J Dermatol 16(1):12–16

    CAS  PubMed  Google Scholar 

  3. Basu S, Fenton MJ (2004) Toll-like receptors: function and roles in lung disease. Am J Phys Lung Cell Mol Phys 286(5):L887–L892

    CAS  Google Scholar 

  4. O’Neill LA, Dinarello CA (2000) The IL-1 receptor/toll-like receptor superfamily: crucial receptors for inflammation and host defense. Immunol Today 21(5):206–209

    Article  PubMed  Google Scholar 

  5. Smirnova I, Poltorak A, Chan EK et al (2000) Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4). Genome Biol 1(1):research002. 1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lai C-Y, Yu G-Y, Luo Y et al (2019) Immunostimulatory activities of CpG-oligodeoxynucleotides in teleosts: toll-like receptors 9 and 21. Front Immunol 10:179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang J, Yan H (2017) TLR5: beyond the recognition of flagellin. Cell Mol Immunol 14(12):1017–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Blaser H, Dostert C, Mak TW et al (2016) TNF and ROS crosstalk in inflammation. Trends Cell Biol 26(4):249–261

    Article  CAS  PubMed  Google Scholar 

  9. Haider T, Tiwari R, Vyas SP et al (2019) Molecular determinants as therapeutic targets in cancer chemotherapy: an update. Pharmacol Ther 200:85–109

    Article  CAS  PubMed  Google Scholar 

  10. Shchebliakov D, Logunov DY, Tukhvatulin A et al (2010) Toll-like receptors (TLRs): the role in tumor progression. Acta Nat 2(3):6

    Article  Google Scholar 

  11. Monlish DA, Bhatt ST, Schuettpelz LG (2016) The role of toll-like receptors in hematopoietic malignancies. Front Immunol 7:390

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Yang Y, Lv J, Jiang S et al (2016) The emerging role of toll-like receptor 4 in myocardial inflammation. Cell Death Dis 7(5):e2234–e2234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li M, Zhou Y, Feng G et al (2009) The critical role of toll-like receptor signaling pathways in the induction and progression of autoimmune diseases. Curr Mol Med 9(3):365–374

    Article  CAS  PubMed  Google Scholar 

  14. Curtiss LK, Tobias PS (2009) Emerging role of toll-like receptors in atherosclerosis. J Lipid Res 50(Supplement):S340–S345

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Kovach MA, Standiford TJ (2011) Toll like receptors in diseases of the lung. Int Immunopharmacol 11(10):1399–1406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lafferty EI, Qureshi ST, Schnare M (2010) The role of toll-like receptors in acute and chronic lung inflammation. J Inflamm 7(1):57

    Article  CAS  Google Scholar 

  17. Grassin-Delyle S, Abrial C, Salvator H et al (2020) The role of toll-like receptors in the production of cytokines by human lung macrophages. J Innate Immun 12(1):63–73

    Article  CAS  PubMed  Google Scholar 

  18. Sidletskaya K, Vitkina T, Denisenko Y (2020) The role of toll-like receptors 2 and 4 in the pathogenesis of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 15:1481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bhagwani A, Thompson AR, Farkas L (2020) When innate immunity meets angiogenesis—the role of toll-like receptors in endothelial cells and pulmonary hypertension. Front Med 7

    Google Scholar 

  20. Arora S, Ahmad S, Irshad R et al (2019) TLRs in pulmonary diseases. Life Sci 233:116671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Christmas P (2010) Toll-like receptors: sensors that detect infection. Nat Educ 3(9):85

    Google Scholar 

  22. Sharma S, Garg I, Ashraf MZ (2016) TLR signalling and association of TLR polymorphism with cardiovascular diseases. Vasc Pharmacol 87:30–37

    Article  CAS  Google Scholar 

  23. Sha Q, Truong-Tran AQ, Plitt JR et al (2004) Activation of airway epithelial cells by toll-like receptor agonists. Am J Respir Cell Mol Biol 31(3):358–364

    Article  PubMed  CAS  Google Scholar 

  24. Hoppstädter J, Diesel B, Zarbock R et al (2010) Differential cell reaction upon toll-like receptor 4 and 9 activation in human alveolar and lung interstitial macrophages. Respir Res 11(1):124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Farkas D, Thompson AR, Bhagwani AR et al (2019) Toll-like receptor 3 is a therapeutic target for pulmonary hypertension. Am J Respir Crit Care Med 199(2):199–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang MM, Lu M, Zhang CL et al (2018) Oxidative stress modulates the expression of toll-like receptor 3 during respiratory syncytial virus infection in human lung epithelial A549 cells. Mol Med Rep 18(2):1867–1877

    CAS  PubMed  Google Scholar 

  27. Esawy MM, Shabana MA, Baioumy SA et al (2019) Diagnostic and prognostic roles of peripheral blood toll-like receptor-4 and stanniocalcin-1 genes expression in acute lung injury. Immunobiology 224(6):734–738

    Article  CAS  PubMed  Google Scholar 

  28. Tang S-E, Wu S-Y, Chu S-J et al (2019) Pre-treatment with ten-minute carbon dioxide inhalation prevents lipopolysaccharide-induced lung injury in mice via down-regulation of toll-like receptor 4 expression. Int J Mol Sci 20(24):6293

    Article  CAS  PubMed Central  Google Scholar 

  29. Andonegui G, Bonder CS, Green F et al (2003) Endothelium-derived toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs. J Clin Invest 111(7):1011–1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Samara KD, Antoniou KM, Karagiannis K et al (2012) Expression profiles of toll-like receptors in non-small cell lung cancer and idiopathic pulmonary fibrosis. Int J Oncol 40(5):1397–1404

    CAS  PubMed  Google Scholar 

  31. Zhou H, Chen JH, Hu J et al (2014) High expression of toll-like receptor 5 correlates with better prognosis in non-small-cell lung cancer: an antitumor effect of TLR5 signaling in non-small cell lung cancer. J Cancer Res Clin Oncol 140(4):633–643

    Article  CAS  PubMed  Google Scholar 

  32. Koller B, Kappler M, Latzin P et al (2008) TLR expression on neutrophils at the pulmonary site of infection: TLR1/TLR2-mediated up-regulation of TLR5 expression in cystic fibrosis lung disease. J Immunol 181(4):2753–2763

    Article  CAS  PubMed  Google Scholar 

  33. Plantinga M, Hammad H, Lambrecht BN (2010) Origin and functional specializations of DC subsets in the lung. Eur J Immunol 40(8):2112–2118

    Article  CAS  PubMed  Google Scholar 

  34. Lee K, Kim SH, Yoon HJ et al (2011) Bacillus-derived poly-gamma-glutamic acid attenuates allergic airway inflammation through a toll-like receptor-4-dependent pathway in a murine model of asthma. Clin Exp Allergy 41(8):1143–1156

    Article  CAS  PubMed  Google Scholar 

  35. Arancibia SA, Beltrán CJ, Aguirre IM et al (2007) Toll-like receptors are key participants in innate immune responses. Biol Res 40(2):97–112

    Article  CAS  PubMed  Google Scholar 

  36. Chen ZJ (2005) Ubiquitin signalling in the NF-κB pathway. Nat Cell Biol 7(8):758–765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Collins SE, Noyce RS, Mossman KL (2004) Innate cellular response to virus particle entry requires IRF3 but not virus replication. J Virol 78(4):1706–1717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. El-Zayat SR, Sibaii H, Mannaa FA (2019) Toll-like receptors activation, signaling, and targeting: an overview. Bull Natl Res Cent 43(1):187

    Article  Google Scholar 

  39. Banno A, Reddy AT, Lakshmi SP et al (2020) Bidirectional interaction of airway epithelial remodeling and inflammation in asthma. Clin Sci 134(9):1063–1079

    Article  CAS  Google Scholar 

  40. Zakeri A, Yazdi FG (2017) Toll-like receptor-mediated involvement of innate immune cells in asthma disease. Biochim Biophys Acta 1861(1):3270–3277

    Article  CAS  Google Scholar 

  41. Herrick CA, Bottomly K (2003) To respond or not to respond: T cells in allergic asthma. Nat Rev Immunol 3(5):405–412

    Article  CAS  PubMed  Google Scholar 

  42. Conrad ML, Ferstl R, Teich R et al (2009) Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J Exp Med 206(13):2869–2877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Møller-Larsen S, Nyegaard M, Haagerup A et al (2008) Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders. Thorax 63(12):1064–1069

    Article  PubMed  Google Scholar 

  44. Genuneit J, Cantelmo J, Weinmayr G et al (2009) A multi-centre study of candidate genes for wheeze and allergy: the International Study of Asthma and Allergies in Childhood Phase 2. Clin Exp Allergy 39(12):1875–1888

    Article  CAS  PubMed  Google Scholar 

  45. Brooks LR, Mias GI (2018) Streptococcus pneumoniae’s virulence and host immunity: aging, diagnostics, and prevention. Front Immunol 9:1366

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Acosta PL, Caballero MT, Polack FP (2016) Brief history and characterization of enhanced respiratory syncytial virus disease. Clin Vaccine Immunol 23(3):189–195

    Article  CAS  PubMed Central  Google Scholar 

  47. Pinto A, Morello S, Sorrentino R (2011) Lung cancer and toll-like receptors. Cancer Immunol Immunother 60(9):1211

    Article  CAS  PubMed  Google Scholar 

  48. Ren T, Xu L, Jiao S et al (2009) TLR9 signaling promotes tumor progression of human lung cancer cell in vivo. Pathol Oncol Res 15(4):623–630

    Article  CAS  PubMed  Google Scholar 

  49. Sarir H, Mortaz E, Karimi K et al (2009) Cigarette smoke regulates the expression of TLR4 and IL-8 production by human macrophages. J Inflamm 6(1):12

    Article  Google Scholar 

  50. Welsh TJ, Green RH, Richardson D et al (2005) Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non–small-cell lung cancer. J Clin Oncol 23(35):8959–8967

    Article  PubMed  Google Scholar 

  51. Oldford SA, Haidl ID, Howatt MA et al (2010) A critical role for mast cells and mast cell-derived IL-6 in TLR2-mediated Inhibition of tumor growth. J Immunol 185(11):7067–7076

    Article  CAS  PubMed  Google Scholar 

  52. Zhang X, Shan P, Jiang G et al (2006) Toll-like receptor 4 deficiency causes pulmonary emphysema. J Clin Invest 116(11):3050–3059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Doz E, Noulin N, Boichot E et al (2008) Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent. J Immunol 180(2):1169–1178

    Article  CAS  PubMed  Google Scholar 

  54. Karimi K, Sarir H, Mortaz E et al (2006) Toll-like receptor-4 mediates cigarette smoke-induced cytokine production by human macrophages. Respir Res 7(1):66

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Maes T, Bracke KR, Vermaelen KY et al (2006) Murine TLR4 is implicated in cigarette smoke-induced pulmonary inflammation. Int Arch Allergy Immunol 141(4):354–368

    Article  PubMed  Google Scholar 

  56. Chaudhuri N, Dower SK, Whyte MK et al (2005) Toll-like receptors and chronic lung disease. Clin Sci (Lond) 109(2):125–133

    Article  CAS  Google Scholar 

  57. Knapp S, Wieland CW, van’t Veer C et al (2004) Toll-like receptor 2 plays a role in the early inflammatory response to murine pneumococcal pneumonia but does not contribute to antibacterial defense. J Immunol 172(5):3132–3138

    Article  CAS  PubMed  Google Scholar 

  58. Chaudhuri N, Dower SK, Whyte MK et al (2005) Toll-like receptors and chronic lung disease. Clin Sci 109(2):125–133

    Article  CAS  Google Scholar 

  59. Baral P, Batra S, Zemans RL et al (2014) Divergent functions of toll-like receptors during bacterial lung infections. Am J Respir Crit Care Med 190(7):722–732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Delneste Y, Beauvillain C, Jeannin P (2007) Immunité naturelle-Structure et fonction des toll-like receptors. Médecine/Sciences 23(1):67–74

    Article  Google Scholar 

  61. Ayres JS, Schneider DS (2012) Tolerance of infections. Annu Rev Immunol 30:271–294

    Article  CAS  PubMed  Google Scholar 

  62. Murad S (2014) Toll-like receptor 4 in inflammation and angiogenesis: a double-edged sword. Front Immunol 5:313

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4(7):499–511

    Article  CAS  PubMed  Google Scholar 

  64. Yamamoto M, Takeda K (2010) Current views of toll-like receptor signaling pathways. Gastroenterol Res Pract 2010

    Google Scholar 

  65. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34(5):637–650

    Article  CAS  PubMed  Google Scholar 

  66. Gao W, Xiong Y, Li Q et al (2017) Inhibition of toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front Physiol 8:508

    Article  PubMed  PubMed Central  Google Scholar 

  67. Kužnik A, Benčina M, Švajger U et al (2011) Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol 186(8):4794–4804

    Article  PubMed  CAS  Google Scholar 

  68. Daubeuf B, Mathison J, Spiller S et al (2007) TLR4/MD-2 monoclonal antibody therapy affords protection in experimental models of septic shock. J Immunol 179(9):6107–6114

    Article  CAS  PubMed  Google Scholar 

  69. Zhu F-G, Jiang W, Dong Y et al (2012) IMO-8400, a novel TLR7, TLR8 and TLR9 antagonist, inhibits disease development in lupus-prone NZBW/F1 mice (119.12). Am Assoc Immnol

    Google Scholar 

  70. Opal SM, Laterre P-F, Francois B et al (2013) Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309(11):1154–1162

    Article  CAS  PubMed  Google Scholar 

  71. Shen N, Liang D, Tang Y et al (2012) MicroRNAs—novel regulators of systemic lupus erythematosus pathogenesis. Nat Rev Rheumatol 8(12):701–709

    Article  CAS  PubMed  Google Scholar 

  72. Babazada H, Yamashita F, Yanamoto S et al (2014) Self-assembling lipid modified glycol-split heparin nanoparticles suppress lipopolysaccharide-induced inflammation through TLR4–NF-κB signaling. J Control Release 194:332–340

    Article  CAS  PubMed  Google Scholar 

  73. Shalaby KH, Jo T, Nakada E et al (2012) ICOS-expressing CD4 T cells induced via TLR4 in the nasal mucosa are capable of inhibiting experimental allergic asthma. J Immunol 189(6):2793–2804

    Article  CAS  PubMed  Google Scholar 

  74. Xirakia C, Koltsida O, Stavropoulos A et al (2010) Toll-like receptor 7–triggered immune response in the lung mediates acute and long-lasting suppression of experimental asthma. Am J Respir Crit Care Med 181(11):1207–1216

    Article  CAS  PubMed  Google Scholar 

  75. G Drake M, H Kaufman E, D Fryer A et al (2012) The therapeutic potential of toll-like receptor 7 stimulation in asthma. Inflamm Allergy-Drug Targets 11(6):484–491

    Article  Google Scholar 

  76. Zuo L, Lucas K, Fortuna CA et al (2015) Molecular regulation of toll-like receptors in asthma and COPD. Front Physiol 6:312

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, Madhya Pradesh, India

    Indu Lata Kanwar, Tanweer Haider, Vikas Pandey & Vandana Soni

  2. Formulation and Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India

    Prem N. Gupta

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  1. Indu Lata Kanwar
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  2. Tanweer Haider
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  3. Vikas Pandey
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  4. Prem N. Gupta
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  5. Vandana Soni
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Correspondence to Vandana Soni .

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Editors and Affiliations

  1. Graduate School of Health, Discipline of Pharmacy, University of Technology Sydney, Sydney, NSW, Australia

    Kamal Dua

  2. Drug Development and Innovation Centre, University of Alberta, Edmonton, AB, Canada

    Raimar Löbenberg

  3. Haematology and Hemotherapy Center, State University of Campinas, Campinas, São Paulo, Brazil

    Ângela Cristina Malheiros Luzo

  4. Graduate School of Health, Discipline of Pharmacy, University of Technology Sydney, Sydney, NSW, Australia

    Shakti Shukla

  5. School of Pharmaceutical Sciences & Division of Research & Development, Lovely Professional University, Phagwara, Punjab, India

    Saurabh Satija

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Kanwar, I.L., Haider, T., Pandey, V., Gupta, P.N., Soni, V. (2021). Role of Toll-Like Receptors in Molecular and Cellular Mechanisms of Respiratory Diseases. In: Dua, K., Löbenberg, R., Malheiros Luzo, Â.C., Shukla, S., Satija, S. (eds) Targeting Cellular Signalling Pathways in Lung Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-33-6827-9_31

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