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01-12-2021 | Mites | Research

PGC-1α regulates airway epithelial barrier dysfunction induced by house dust mite

Authors: Tsutomu Saito, Tomohiro Ichikawa, Tadahisa Numakura, Mitsuhiro Yamada, Akira Koarai, Naoya Fujino, Koji Murakami, Shun Yamanaka, Yusaku Sasaki, Yorihiko Kyogoku, Koji Itakura, Hirohito Sano, Katsuya Takita, Rie Tanaka, Tsutomu Tamada, Masakazu Ichinose, Hisatoshi Sugiura

Published in: Respiratory Research | Issue 1/2021

Abstract

Background

The airway epithelial barrier function is disrupted in the airways of asthmatic patients. Abnormal mitochondrial biogenesis is reportedly involved in the pathogenesis of asthma. However, the role of mitochondrial biogenesis in the airway barrier dysfunction has not been elucidated yet. This study aimed to clarify whether the peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a central regulator of mitochondrial biogenesis, is involved in the disruption of the airway barrier function induced by aeroallergens.

Methods

BEAS-2B cells were exposed to house dust mite (HDM) and the expressions of PGC-1α and E-cadherin, a junctional protein, were examined by immunoblotting. The effect of SRT1720, a PGC-1α activator, was investigated by immunoblotting, immunocytochemistry, and measuring the transepithelial electrical resistance (TEER) on the HDM-induced reduction in mitochondrial biogenesis markers and junctional proteins in airway bronchial epithelial cells. Furthermore,the effects of protease activated receptor 2 (PAR2) inhibitor, GB83, Toll-like receptor 4 (TLR4) inhibitor, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), protease inhibitors including E64 and 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) on the HDM-induced barrier dysfunction were investigated.

Results

The amounts of PGC-1α and E-cadherin in the HDM-treated cells were significantly decreased compared to the vehicle-treated cells. SRT1720 restored the expressions of PGC-1α and E-cadherin reduced by HDM in BEAS-2B cells. Treatment with SRT1720 also significantly ameliorated the HDM-induced reduction in TEER. In addition, GB83, LPS-RS, E64 and AEBSF prevented the HDM-induced reduction in the expression of PGC1α and E-cadherin.

Conclusions

The current study demonstrated that HDM disrupted the airway barrier function through the PAR2/TLR4/PGC-1α-dependent pathway. The modulation of this pathway could be a new approach for the treatment of asthma.

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Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention 2019. https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf. Acceced 1 Jul 2019.

Leόn B. T cells in allergic asthma: key players beyond the Th2 pathway. Curr Allergy Asthma Rep. 2017. https://doi.org/10.1007/s11882-017-0714-1.CrossRefPubMed

Robinson DS. The role of the T cell in asthma. J Allergy Clin Immunol. 2010;126(6):1081–91. https://doi.org/10.1016/j.jaci.2010.06.025.CrossRefPubMed

Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15(1):57–65. https://doi.org/10.1038/nri3786.CrossRefPubMedPubMedCentral

Georas SN, Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation. J Allergy Clin Immunol. 2014;134(3):509–20. https://doi.org/10.1016/j.jaci.2014.05.049.CrossRefPubMedPubMedCentral

Zihni C, Mills C, Matter K, Balda MS. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol. 2016;17(9):564–80. https://doi.org/10.1038/nrm.2016.80.CrossRefPubMed

Xiao C, Puddicombe SM, Field S, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol. 2011. https://doi.org/10.1016/j.jaci.2011.05.038.CrossRefPubMed

Shishikura Y, Koarai A, Aizawa H, et al. Extracellular ATP is involved in dsRNA-induced MUC5AC production via P2Y2R in human airway epithelium. Respir Res. 2016;17(1):1–14. https://doi.org/10.1186/s12931-016-0438-0.CrossRef

Kuruvilla ME, Lee FE-H, Lee GB. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol. 2019;56(2):219–33. https://doi.org/10.1007/s12016-018-8712-1.CrossRefPubMedPubMedCentral

10.

Frey A, Lunding LP, Ehlers JC, Weckmann M, Zissler UM, Wegmann M. More than just a barrier: the immune functions of the airway epithelium in asthma pathogenesis. Front Immunol. 2020;11(April):1–22. https://doi.org/10.3389/fimmu.2020.00761.CrossRef

11.

Hellings PW, Steelant B. Epithelial barriers in allergy and asthma. J Allergy Clin Immunol. 2020;145(6):1499–509. https://doi.org/10.1016/j.jaci.2020.04.010.CrossRefPubMedPubMedCentral

12.

Pattnaik B, Bodas M, Bhatraju NK, et al. IL-4 promotes asymmetric dimethylarginine accumulation, oxo-nitrative stress, and hypoxic response-induced mitochondrial loss in airway epithelial cells. J Allergy Clin Immunol. 2016;138(1):130-141.e9. https://doi.org/10.1016/j.jaci.2015.11.036.CrossRefPubMed

13.

Gureev AP, Shaforostova EA, Popov VN. Regulation of mitochondrial biogenesis as a way for active longevity : interaction between the Nrf2 and PGC-1 α signaling pathways. Front Genet. 2019. https://doi.org/10.3389/fgene.2019.00435.CrossRefPubMedPubMedCentral

14.

Piantadosi CA, Suliman HB. Mitochondrial dysfunction in lung pathogenesis. Annu Rev Physiol. 2017;79:495–515. https://doi.org/10.1146/annurev-physiol-022516-034322.CrossRefPubMed

15.

Wu Z, Puigserver P, Andersson U, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999;98(1):115–24. https://doi.org/10.1016/S0092-8674(00)80611-X.CrossRefPubMed

16.

Sepharose PG, Rodgers JT, Lerin C, et al. Nutrient control of glucose homeostasis through a complex of PGC-1 a and SIRT1. Nature. 2005;434(March):3–8. https://doi.org/10.1038/nature03314.1.CrossRef

17.

Wan X, Wen JJ, Koo SJ, Liang LY, Garg NJ. SIRT1-PGC1alpha-NFkappaB pathway of oxidative and inflammatory stress during trypanosoma cruzi infection: benefits of SIRT1-targeted therapy in improving heart function in chagas disease. PLoS Pathog. 2016;12(10):e1005954. https://doi.org/10.1371/journal.ppat.1005954.CrossRefPubMedPubMedCentral

18.

Funk JA, Odejinmi S, Schnellmann RG. SRT1720 induces mitochondrial biogenesis and rescues mitochondrial function after oxidant injury in renal proximal tubule cells. J Pharmacol Exp Ther. 2010;333(2):593–601. https://doi.org/10.1124/jpet.109.161992.CrossRefPubMedPubMedCentral

19.

Svensson K, Schnyder S, Albert V, et al. Resveratrol and SRT1720 elicit differential effects in metabolic organs and modulate systemic parameters independently of skeletal muscle peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha). J Biol Chem. 2015;290(26):16059–76. https://doi.org/10.1074/jbc.M114.590653.CrossRefPubMedPubMedCentral

20.

Gu C, Li Y, Xu WL, et al. Sirtuin 1 activator SRT1720 protects against lung injury via reduction of type II alveolar epithelial cells apoptosis in emphysema. COPD J Chronic Obstr Pulm Dis. 2015;12(4):444–52. https://doi.org/10.3109/15412555.2014.974740.CrossRef

21.

Zeng Z, Cheng S, Chen H, et al. Activation and overexpression of Sirt1 attenuates lung fibrosis via P300. Biochem Biophys Res Commun. 2017;486(4):1021–6. https://doi.org/10.1016/j.bbrc.2017.03.155.CrossRefPubMed

22.

Yao H, Sundar IK, Huang Y, et al. Disruption of sirtuin 1-mediated control of circadian molecular clock and inflammation in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2015;53(6):782–92. https://doi.org/10.1165/rcmb.2014-0474OC.CrossRefPubMedPubMedCentral

23.

Ichikawa T, Hayashi R, Suzuki K, et al. Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma. Respirology. 2013;18(2):332–9. https://doi.org/10.1111/j.1440-1843.2012.02284.x.CrossRefPubMed

24.

Ishii T, Niikura Y, Kurata K, et al. Time-dependent distinct roles of Toll-like receptor 4 in a house dust mite-induced asthma mouse model. Scand J Immunol. 2018;87(3):1–7. https://doi.org/10.1111/sji.12641.CrossRef

25.

Chan TK, Loh XY, Peh HY, et al. House dust mite–induced asthma causes oxidative damage and DNA double-strand breaks in the lungs. J Allergy Clin Immunol. 2016;138(1):84-96.e1. https://doi.org/10.1016/j.jaci.2016.02.017.CrossRefPubMed

26.

Stewart CE, Torr EE, Mohd Jamili NH, Bosquillon C, Sayers I. Evaluation of differentiated human bronchial epithelial cell culture systems for asthma research. j Allergy. 2012. https://doi.org/10.1155/2012/943982.CrossRef

27.

Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity. 2015;43(1):29–40. https://doi.org/10.1016/j.immuni.2015.07.007.CrossRefPubMed

28.

Zhou Y, Wang S, Li Y, et al. Epithelial cell – derived cytokines : more than just signaling the alarm Find the latest version : Epithelial cell – derived cytokines : more than just signaling the alarm. J Clin Invest. 2019;129(4):1441–51. https://doi.org/10.1097/MOL.0b013e328328d0a4.PGC-1alpha.CrossRef

29.

Caminati M, Le PD, Bagnasco D, Canonica GW. Type 2 immunity in asthma. World Allergy Organ J. 2018;11(1):1–10. https://doi.org/10.1186/s40413-018-0192-5.CrossRef

30.

Liang D, Zhuo Y, Guo Z, et al. SIRT1/PGC-1 pathway activation triggers autophagy/mitophagy and attenuates oxidative damage in intestinal epithelial cells. Biochimie. 2020;170:10–20. https://doi.org/10.1016/j.biochi.2019.12.001.CrossRefPubMed

31.

Cunningham KE, Vincent G, Sodhi CP, et al. Peroxisome Proliferator-activated Receptor-γ Coactivator 1-α (PGC1α) Protects against Experimental Murine Colitis. J Biol Chem. 2016;291(19):10184–200. https://doi.org/10.1074/jbc.M115.688812.CrossRefPubMedPubMedCentral

32.

Trian T, Benard G, Begueret H, et al. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med. 2007;204(13):3173–81. https://doi.org/10.1084/jem.20070956.CrossRefPubMedPubMedCentral

33.

Fang L, Wang X, Sun Q, et al. IgE downregulates PTEN through microRNA-21-5p and stimulates airway smooth muscle cell remodeling. Int J Mol Sci. 2019;20(4):1–20. https://doi.org/10.3390/ijms20040875.CrossRef

34.

Davies DE. The role of the epithelium in airway remodeling in asthma. Proc Am Thorac Soc. 2009;6(8):678–82. https://doi.org/10.1513/pats.200907-067DP.CrossRefPubMedPubMedCentral

35.

Lambrecht BN, Hammad H. Allergens and the airway epithelium response: gateway to allergic sensitization. J Allergy Clin Immunol. 2014;134(3):499–507. https://doi.org/10.1016/j.jaci.2014.06.036.CrossRefPubMed

36.

Salazar F, Ghaemmaghami AM. Allergen recognition by innate immune cells: critical role of dendritic and epithelial cells. Front Immunol. 2013;4:356. https://doi.org/10.3389/fimmu.2013.00356.CrossRefPubMedPubMedCentral

37.

Nawijn MC, Hackett TL, Postma DS, van Oosterhout AJ, Heijink IH. E-cadherin: gatekeeper of airway mucosa and allergic sensitization. Trends Immunol. 2011;32(6):248–55. https://doi.org/10.1016/j.it.2011.03.004.CrossRefPubMed

38.

Jacquet A. Interactions of airway epithelium with protease allergens in the allergic response. Clin Exp Allergy. 2011;41(3):305–11. https://doi.org/10.1111/j.1365-2222.2010.03661.x.CrossRefPubMed

39.

Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med. 2009;15(4):410–6. https://doi.org/10.1038/nm.1946.CrossRefPubMedPubMedCentral

40.

Rallabhandi P, Nhu QM, Toshchakov VY, et al. Analysis of proteinase-activated receptor 2 and TLR4 signal transduction: a novel paradigm for receptor cooperativity. J Biol Chem. 2008;283(36):24314–25. https://doi.org/10.1074/jbc.M804800200.CrossRefPubMedPubMedCentral

41.

Yuan S, Liu X, Zhu X, et al. The role of TLR4 on PGC-1α-mediated oxidative stress in tubular cell in diabetic kidney disease. Oxid Med Cell Longev. 2018;2018:1–14. https://doi.org/10.1155/2018/6296802.CrossRef

42.

Wan H, Winton HL, Soeller C, et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest. 1999;104(1):123–33. https://doi.org/10.1172/JCI5844.CrossRefPubMedPubMedCentral

43.

Henriquez OA, Den BK, Hoddeson EK, Parkos CA, Nusrat A, Wise SK. House dust mite allergen Der p 1 effects on sinonasal epithelial tight junctions. Int Forum Allergy Rhinol. 2013;3(8):630–5. https://doi.org/10.1002/alr.21168.CrossRefPubMedPubMedCentral

44.

Heijink IH, Van Oosterhout A, Kapus A. Epidermal growth factor receptor signalling contributes to house dust mite-induced epithelial barrier dysfunction. Eur Respir J. 2010;36(5):1016–26. https://doi.org/10.1183/09031936.00125809.CrossRefPubMed

45.

Zheng J, Liu W, Fan Y, et al. Suppression of connexin 26 is related to protease-activated receptor 2-mediated pathway in patients with allergic rhinitis. Am J Rhinol Allergy. 2012;26(1):5–9. https://doi.org/10.2500/ajra.2012.26.3740.CrossRef

46.

Heyen L, Müller U, Siegemund S, et al. Lung epithelium is the major source of IL-33 and is regulated by IL-33-dependent and IL-33-independent mechanisms in pulmonary cryptococcosis. Pathog Dis. 2016;74(7):1–11. https://doi.org/10.1093/femspd/ftw086.CrossRef

47.

Stotland A, Gottlieb RA. Mitochondrial quality control: easy come, easy go. Biochim Biophys Acta Mol Cell Res. 2015;1853(10):2802–11. https://doi.org/10.1016/j.bbamcr.2014.12.041.CrossRef

48.

Int C, Wang L, Wang M, Dou H, Lin W, Zou L. Sirtuin 1 inhibits lipopolysaccharide - induced inflammation in chronic myelogenous leukemia k562 cells through interacting with the Toll like receptor 4-nuclear factor κ B-reactive oxygen species signaling axis. Cancer Cell Int. 2020. https://doi.org/10.1186/s12935-020-1152-z.CrossRef

49.

Li X, Jamal M, Guo P, et al. Irisin alleviates pulmonary epithelial barrier dysfunction in sepsis-induced acute lung injury via activation of AMPK/SIRT1 pathways. Biomed Pharmacother. 2019;118(June):109363. https://doi.org/10.1016/j.biopha.2019.109363.CrossRefPubMed

50.

Li Y, Deng S-L, Lian Z-X, Yu K. Roles of Toll-Like Receptors in Nitroxidative Stress in Mammals. Cells. 2019;8(6):576. https://doi.org/10.3390/cells8060576.CrossRefPubMedCentral

51.

Gill R, Tsung A, Billiar T. Linking oxidative stress to inflammation: toll-like receptors. Free Radic Biol Med. 2010;48(9):1121–32. https://doi.org/10.1016/j.freeradbiomed.2010.01.006.CrossRefPubMedPubMedCentral

52.

Ichikawa T, Sugiura H, Koarai A, et al. TLR3 activation augments matrix metalloproteinase production through reactive nitrogen species generation in human lung fibroblasts. J Immunol. 2014;192(11):4977–88. https://doi.org/10.4049/jimmunol.1302919.CrossRefPubMed

53.

Salminen A, Kaarniranta K, Kauppinen A. Crosstalk between oxidative stress and SIRT1: impact on the aging process. Int J Mol Sci. 2013;14(2):3834–59. https://doi.org/10.3390/ijms14023834.CrossRefPubMedPubMedCentral

54.

Chen Z, Shentu TP, Wen L, Johnson DA, Shyy JYJ. Regulation of SIRT1 by oxidative stress-responsive miRNAs and a systematic approach to identify its role in the endothelium. Antioxidants Redox Signal. 2013;19(13):1522–38. https://doi.org/10.1089/ars.2012.4803.CrossRef

55.

Sugiura H, Ichinose M. Oxidative and nitrative stress in bronchial asthma. Antioxidants Redox Signal. 2008;10(4):785–97. https://doi.org/10.1089/ars.2007.1937.CrossRef

56.

Nakazawa H, Chang K, Shinozaki S, et al. iNOS as a driver of inflammation and apoptosis in mouse skeletal muscle after burn injury: Possible involvement of sirt1 S- nitrosylation-mediated acetylation of p65 NFeΚB and p53. PLoS ONE. 2017;12(1):1–18. https://doi.org/10.1371/journal.pone.0170391.CrossRef

57.

Wells SM, Holian A. Asymmetric dimethylarginine induces oxidative and nitrosative stress in murine lung epithelial cells. Am J Respir Cell Mol Biol. 2007;36(5):520–8. https://doi.org/10.1165/rcmb.2006-0302SM.CrossRefPubMed

58.

Melser S, Lavie J, Bénard G. Mitochondrial degradation and energy metabolism. Biochim Biophys Acta - Mol Cell Res. 2015;1853(10):2812–21. https://doi.org/10.1016/j.bbamcr.2015.05.010.CrossRef

59.

Ploumi C, Daskalaki I, Tavernarakis N. Mitochondrial biogenesis and clearance: a balancing act. FEBS J. 2017;284(2):183–95. https://doi.org/10.1111/febs.13820.CrossRefPubMed

60.

Benischke AS, Vasanth S, Miyai T, et al. Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy. Sci Rep. 2017;7(1):1–11. https://doi.org/10.1038/s41598-017-06523-2.CrossRef

61.

Palikaras K, Lionaki E, Tavernarakis N. Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis. Cell Death Differ. 2015;22(9):1399–401. https://doi.org/10.1038/cdd.2015.86.CrossRefPubMedPubMedCentral

62.

Gershwin LJ. Effects of allergenic extracts on airway epithelium. Curr Allergy Asthma Rep. 2007;7(5):357–62. https://doi.org/10.1007/s11882-007-0054-7.CrossRefPubMed

63.

Chevigné A, Jacquet A. Emerging roles of the protease allergen Der p 1 in house dust mite–induced airway inflammation. J Allergy Clin Immunol. 2018;142(2):398–400. https://doi.org/10.1016/j.jaci.2018.05.027.CrossRefPubMed

64.

Hyde EJ, Wakelin KA, Daniels NJ, Ghosh S, Ronchese F. Similar immune mechanisms control experimental airway eosinophilia elicited by different allergens and treatment protocols. BMC Immunol. 2019;20(1):1–14. https://doi.org/10.1186/s12865-019-0295-y.CrossRef

65.

Cipriani F, Calamelli E, Ricci G. Allergen avoidance in allergic asthma. Front Pediatr. 2017. https://doi.org/10.3389/fped.2017.00103.CrossRefPubMedPubMedCentral

66.

Posa D, Perna S, Resch Y, et al. Evolution and predictive value of IgE responses toward a comprehensive panel of house dust mite allergens during the first 2 decades of life. J Allergy Clin Immunol. 2017;139(2):541-549.e8. https://doi.org/10.1016/j.jaci.2016.08.014.CrossRefPubMed

67.

Tsai Y, Chiang K, Hung J, et al. Der f1 induces pyroptosis in human bronchial epithelia via the NLRP3 inflammasome. Int J Mol Med. 2017;41(2):757–64. https://doi.org/10.3892/ijmm.2017.3310.CrossRefPubMedPubMedCentral

68.

Blume C, Davies DE. In vitro and ex vivo models of human asthma. Eur J Pharm Biopharm. 2013;84(2):394–400. https://doi.org/10.1016/j.ejpb.2012.12.014.CrossRefPubMed

Title: PGC-1α regulates airway epithelial barrier dysfunction induced by house dust mite
Authors: Tsutomu Saito
Tomohiro Ichikawa
Tadahisa Numakura
Mitsuhiro Yamada
Akira Koarai
Naoya Fujino
Koji Murakami
Shun Yamanaka
Yusaku Sasaki
Yorihiko Kyogoku
Koji Itakura
Hirohito Sano
Katsuya Takita
Rie Tanaka
Tsutomu Tamada
Masakazu Ichinose
Hisatoshi Sugiura
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Mites
Bronchial Asthma
Published in: Respiratory Research / Issue 1/2021
Electronic ISSN: 1465-993X
DOI: https://doi.org/10.1186/s12931-021-01663-6

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