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TLR2 Regulates Allergic Airway Inflammation and Autophagy Through PI3K/Akt Signaling Pathway

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Abstract

Toll-like receptors (TLRs) are innate pattern recognition receptors that play a critical role in allergic inflammation, yet their contribution to autophagy in asthma remains poorly defined. Here, we investigate the role of Toll-like receptor 2 (TLR2) in phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway-mediated autophagy in ovalbumin-induced airway inflammation in mice. Wild-type (WT) and TLR2-knockout (TLR2−/−) C57BL/6 mice were ovalbumin-sensitized and ovalbumin-challenged. In ovalbumin-challenged WT mice, enhanced expression of TLR2 in lung tissue, remarkable inflammatory cell infiltrates, goblet cell hyperplasia, and increased mucus production were observed. The number of inflammatory cells and interleukin-13 (IL-13) levels increased, while interferon-gamma (IFN-γ) levels decreased in bronchoalveolar lavage fluid. Expression of PI3K, phospho-Akt, Beclin-1 and LC3-II was enhanced significantly. These changes were mitigated dose-dependently in 3-methyl adenine-treated mice. In contrast, similar but weaker changes were found in ovalbumin-challenged TLR2−/− mice, and the changes were not significantly attenuated by 3-methyl adenine treatment. These results indicate that TLR2 confers a pivotal role in allergic airway inflammation via regulating the PI3K/Akt signaling pathway-related autophagy in mice.

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References

  1. Anderson, G.P. 2008. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 372: 1107–1119.

    Article  PubMed  Google Scholar 

  2. Holtzman, M.J. 2012. Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens. The Journal of Clinical Investigation 122: 2741–2748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Holgate, S.T. 2012. Innate and adaptive immune responses in asthma. Nature Medicine 18: 673–683.

    Article  CAS  PubMed  Google Scholar 

  4. Goulopoulou, S., C.G. McCarthy, and R.C. Webb. 2016. Toll-like receptors in the vascular system: sensing the dangers within. Pharmacological Reviews 68: 142–167.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Larsen, J.M., H.S. Musavian, T.M. Butt, C. Ingvorsen, A.H. Thysen, and S. Brix. 2015. Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology. Immunology 144: 333–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shimizu, T., Y. Kimura, Y. Kida, K. Kuwano, M. Tachibana, M. Hashino, et al. 2014. Cytadherence of Mycoplasma pneumoniae induces inflammatory responses through autophagy and toll-like receptor 4. Infection and Immunity 82: 3076–3086.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sanchez-Zauco, N., B. Del Rio-Navarro, C. Gallardo-Casas, J. Del Rio-Chivardi, R. Muriel-Vizcaino, C. Rivera-Pazos, et al. 2014. High expression of Toll-like receptors 2 and 9 and Th1/Th2 cytokines profile in obese asthmatic children. Allergy and Asthma Proceedings 35: 34–41.

    Article  PubMed  Google Scholar 

  8. Page, K., K.M. Lierl, V.S. Hughes, P. Zhou, J.R. Ledford, and M. Wills-Karp. 2008. TLR2-mediated activation of neutrophils in response to German cockroach frass. Journal of Immunology 180: 6317–6324.

    Article  CAS  Google Scholar 

  9. Redecke, V., H. Hacker, S.K. Datta, A. Fermin, P.M. Pitha, D.H. Broide, et al. 2004. Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. Journal of Immunology 172: 2739–2743.

    Article  CAS  Google Scholar 

  10. Page, K., J.R. Ledford, P. Zhou, and M. Wills-Karp. 2009. A TLR2 agonist in German cockroach frass activates MMP-9 release and is protective against allergic inflammation in mice. Journal of Immunology 183: 3400–3408.

    Article  CAS  Google Scholar 

  11. Li, X., Q. Chen, C. Chu, H. You, M. Jin, X. Zhao, et al. 2014. Ovalbumin-induced experimental allergic asthma is Toll-like receptor 2 dependent. Allergy and Asthma Proceedings 35: e15–e20.

    Article  PubMed  Google Scholar 

  12. Chaabane, W., S.D. User, M. El-Gazzah, R. Jaksik, E. Sajjadi, J. Rzeszowska-Wolny, et al. 2013. Autophagy, apoptosis, mitoptosis and necrosis: interdependence between those pathways and effects on cancer. Archivum Immunologiae et Therapiae Experimentalis (Warsz) 61: 43–58.

    Article  CAS  Google Scholar 

  13. Mizumura, K., S.M. Cloonan, J.A. Haspel, and A.M. Choi. 2012. The emerging importance of autophagy in pulmonary diseases. Chest 142: 1289–1299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Poon, A.H., F. Chouiali, S.M. Tse, A.A. Litonjua, S.N. Hussain, C.J. Baglole, et al. 2012. Genetic and histologic evidence for autophagy in asthma pathogenesis. The Journal of Allergy and Clinical Immunology 129: 569–571.

    Article  PubMed  Google Scholar 

  15. Locke, N.R., S.G. Royce, J.S. Wainewright, C.S. Samuel, and M.L. Tang. 2007. Comparison of airway remodeling in acute, subacute, and chronic models of allergic airways disease. American Journal of Respiratory Cell and Molecular Biology 36: 625–632.

    Article  CAS  PubMed  Google Scholar 

  16. Nawijn, M.C., A.C. Motta, R. Gras, S. Shirinbak, H. Maazi, and A.J. van Oosterhout. 2013. TLR-2 activation induces regulatory T cells and long-term suppression of asthma manifestations in mice. PloS One 8: e55307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Koltsida, O., S. Karamnov, K. Pyrillou, T. Vickery, A.D. Chairakaki, C. Tamvakopoulos, et al. 2013. Toll-like receptor 7 stimulates production of specialized pro-resolving lipid mediators and promotes resolution of airway inflammation. EMBO Molecular Medicine 5: 762–775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Camateros, P., M. Tamaoka, M. Hassan, R. Marino, J. Moisan, D. Marion, et al. 2007. Chronic asthma-induced airway remodeling is prevented by toll-like receptor-7/8 ligand S28463. American Journal of Respiratory and Critical Care Medicine 175: 1241–1249.

    Article  CAS  PubMed  Google Scholar 

  19. de Aquino, S.G., S. Abdollahi-Roodsaz, M.I. Koenders, F.A. van de Loo, G.J. Pruijn, R.J. Marijnissen, et al. 2014. Periodontal pathogens directly promote autoimmune experimental arthritis by inducing a TLR2- and IL-1-driven Th17 response. Journal of Immunology 192: 4103–4111.

    Article  Google Scholar 

  20. Thierry, A., S. Giraud, A. Robin, A. Barra, F. Bridoux, V. Ameteau, et al. 2014. The alarmin concept applied to human renal transplantation: evidence for a differential implication of HMGB1 and IL-33. PloS One 9: e88742.

    Article  PubMed  PubMed Central  Google Scholar 

  21. He M, Ichinose T, Song Y, Yoshida Y, Bekki K, Arashidani K, et al. 2016. Desert dust induces TLR signaling to trigger Th2-dominant lung allergic inflammation via a MyD88-dependent signaling pathway. Toxicol Appl Pharmacol.

  22. Pace, E., C. Di Sano, M. Ferraro, A. Bruno, V. Caputo, S. Gallina, et al. 2015. Budesonide increases TLR4 and TLR2 expression in Treg lymphocytes of allergic asthmatics. Pulmonary Pharmacology & Therapeutics 32: 93–100.

    Article  CAS  Google Scholar 

  23. Fransson, M., M. Adner, J. Erjefalt, L. Jansson, R. Uddman, and L.O. Cardell. 2005. Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis. Respiratory Research 6: 100.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Koponen, P., J. Vuononvirta, K. Nuolivirta, M. Helminen, Q. He, and M. Korppi. 2014. The association of genetic variants in toll-like receptor 2 subfamily with allergy and asthma after hospitalization for bronchiolitis in infancy. The Pediatric Infectious Disease Journal 33: 463–466.

    Article  PubMed  Google Scholar 

  25. Kerkhof, M., D.S. Postma, B. Brunekreef, N.E. Reijmerink, A.H. Wijga, J.C. de Jongste, et al. 2010. Toll-like receptor 2 and 4 genes influence susceptibility to adverse effects of traffic-related air pollution on childhood asthma. Thorax 65: 690–697.

    Article  CAS  PubMed  Google Scholar 

  26. Fuchs, B., S. Knothe, S. Rochlitzer, M. Nassimi, M. Greweling, H.D. Lauenstein, et al. 2010. A Toll-like receptor 2/6 agonist reduces allergic airway inflammation in chronic respiratory sensitisation to Timothy grass pollen antigens. International Archives of Allergy and Immunology 152: 131–139.

    Article  CAS  PubMed  Google Scholar 

  27. Ferreira, D.S., R. Annoni, L.F. Silva, M. Buttignol, A.B. Santos, M.C. Medeiros, et al. 2012. Toll-like receptors 2, 3 and 4 and thymic stromal lymphopoietin expression in fatal asthma. Clinical and Experimental Allergy 42: 1459–1471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shieh, Y.H., H.M. Huang, C.C. Wang, C.C. Lee, C.K. Fan, and Y.L. Lee. 2015. Zerumbone enhances the Th1 response and ameliorates ovalbumin-induced Th2 responses and airway inflammation in mice. International Immunopharmacology 24: 383–391.

    Article  CAS  PubMed  Google Scholar 

  29. Barboza, R., N.O. Camara, E. Gomes, A. Sa-Nunes, E. Florsheim, L. Mirotti, et al. 2013. Endotoxin exposure during sensitization to allergens shifts TH2 immunity towards a TH17-mediated airway neutrophilic inflammation: role of TLR4 and TLR2. PloS One 8: e67115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu, C.F., D. Drocourt, G. Puzo, J.Y. Wang, and M. Riviere. 2013. Innate immune response of alveolar macrophage to house dust mite allergen is mediated through TLR2/−4 co-activation. PloS One 8: e75983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Buckland, K.F., E. O'Connor, L.A. Murray, and C.M. Hogaboam. 2008. Toll like receptor-2 modulates both innate and adaptive immune responses during chronic fungal asthma in mice. Inflammation Research 57: 379–387.

    Article  CAS  PubMed  Google Scholar 

  32. Jyothula, S.S., and N.T. Eissa. 2013. Autophagy and role in asthma. Current Opinion in Pulmonary Medicine 19: 30–35.

    Article  CAS  PubMed  Google Scholar 

  33. He, C., and B. Levine. 2010. The beclin 1 interactome. Current Opinion in Cell Biology 22: 140–149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xuan F, Jian J, Lin X, Huang J, Jiao Y, Huang W, et al. 2016. 17-Methoxyl-7-Hydroxy-Benzene-Furanchalcone Ameliorates Myocardial Ischemia/Reperfusion Injury in Rat by Inhibiting Apoptosis and Autophagy Via the PI3K-Akt Signal Pathway. Cardiovasc Toxicol.

  35. Yang, J., Q. Chen, S. Tian, S. Song, F. Liu, Q. Wang, et al. 2015. The role of 1,25-dyhydroxyvitamin D3 in mouse liver ischemia reperfusion injury: regulation of autophagy through activation of MEK/ERK signaling and PTEN/PI3K/Akt/mTORC1 signaling. American Journal of Translational Research 7: 2630–2645.

    PubMed  PubMed Central  Google Scholar 

  36. Nashed, B.F., T. Zhang, M. Al-Alwan, G. Srinivasan, A.J. Halayko, K. Okkenhaug, et al. 2007. Role of the phosphoinositide 3-kinase p110delta in generation of type 2 cytokine responses and allergic airway inflammation. European Journal of Immunology 37: 416–424.

    Article  CAS  PubMed  Google Scholar 

  37. Condliffe, A.M., K.A. Cadwallader, T.R. Walker, R.C. Rintoul, A.S. Cowburn, and E.R. Chilvers. 2000. Phosphoinositide 3-kinase: a critical signalling event in pulmonary cells. Respiratory Research 1: 24–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jing Y, Cai X, Xu Y, Zhu C, Wang L, Wang S, et al. 2016. alpha-Lipoic acids promote the protein synthesis of C2C12 myotubes by the TLR2/PI3K signaling pathway. J Agric Food Chem.

  39. Liu Y, Li JY, Chen ST, Huang HR, Cai H. 2015. The rLrp of mycobacterium tuberculosis inhibits proinflammatory cytokine production and downregulates APC function in mouse macrophages via a TLR2-mediated PI3K/Akt pathway activation-dependent mechanism. Cell Mol Immunol.

  40. Liu, H., Z. Liu, J. Chen, L. Chen, X. He, R. Zheng, et al. 2013. Induction of CCL8/MCP-2 by mycobacteria through the activation of TLR2/PI3K/Akt signaling pathway. PloS One 8: e56815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. AKT. 2013. Serine/threonine protein kinase modulates baicalin-triggered autophagy in human bladder cancer T24 cells. International Journal of Oncology 42: 993–1000.

    Google Scholar 

  42. Cheng, C., W.E. Ho, F.Y. Goh, S.P. Guan, L.R. Kong, W.Q. Lai, et al. 2011. Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway. PloS One 6: e20932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee, K.S., H.K. Lee, J.S. Hayflick, Y.C. Lee, and K.D. Puri. 2006. Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. The FASEB Journal 20: 455–465.

    Article  CAS  PubMed  Google Scholar 

  44. Sykes, A., M.R. Edwards, J. Macintyre, A. Del Rosario, V. Gielen, J. Haas, et al. 2013. TLR3, TLR4 and TLRs7-9 induced interferons are not impaired in airway and blood cells in well controlled asthma. PloS One 8: e65921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Arora, M., S.L. Poe, T.B. Oriss, N. Krishnamoorthy, M. Yarlagadda, S.E. Wenzel, et al. 2010. TLR4/MyD88-induced CD11b+Gr-1 in. F4/80+ non-migratory myeloid cells suppress Th2 effector function in the lung. Mucosal Immunology 3: 578–593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang, M., R.K. Kumar, and P.S. Foster. 2009. Pathogenesis of steroid-resistant airway hyperresponsiveness: interaction between IFN-gamma and TLR4/MyD88 pathways. Journal of Immunology 182: 5107–5115.

    Article  CAS  Google Scholar 

  47. Moisan, J., P. Camateros, T. Thuraisingam, D. Marion, H. Koohsari, P. Martin, et al. 2006. TLR7 ligand prevents allergen-induced airway hyperresponsiveness and eosinophilia in allergic asthma by a MYD88-dependent and MK2-independent pathway. American Journal of Physiology. Lung Cellular and Molecular Physiology 290: L987–L995.

    Article  CAS  PubMed  Google Scholar 

  48. Oka, T., S. Hikoso, O. Yamaguchi, M. Taneike, T. Takeda, T. Tamai, et al. 2012. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485: 251–255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We are grateful to Dr. Jiang-Ning Zhou from the University of Science and Technology of China for the technical assistance. We would like to thank Dr. Zhi-Gang Tian from the University of Science and Technology of China for TLR2−/− mice. This study was supported by the Natural Science Foundation of China (No. 81170030, 81270082, and 81300027), National Education Ministry of China (No. 20113420110006), Annual Research Project of Anhui Province (No. 10021303028), and Key Lab of Geriatric Molecular Medicine of Anhui Province (No. 1206c0805028).

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Jiang, X., Fang, L., Wu, H. et al. TLR2 Regulates Allergic Airway Inflammation and Autophagy Through PI3K/Akt Signaling Pathway. Inflammation 40, 1382–1392 (2017). https://doi.org/10.1007/s10753-017-0581-x

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