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Toll-like receptor activity in patients with obstructive sleep apnea

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Abstract

Background

Obstructive sleep apnea (OSA) has been linked to chronic inflammation and cardiovascular diseases. Considerable evidence suggests that innate immune defense mechanisms might interact with proinflammatory pathways and contribute to atherogenesis. We hypothesized that the classical pathogen recognition receptors of the innate immune response, Toll-like receptors, are involved in modulating the inflammatory response in OSA.

Methods

Expression of TLR2 and TLR4 on circulating monocytes from 29 subjects with documented OSA and 18 controls were compared with the use of flow cytometry and reverse transcription-polymerase chain reaction at baseline and after 8 weeks of continuous positive airway pressure (CPAP).

Results

There was a significant increase in both TLR2 and TLR4 surface expression and mRNA levels on monocytes after adjustment for age, body mass index, and waist-to-hip ratio. This was paralleled by enhanced nuclear factor-κB nuclear binding and an increased release of IL-6, INF-γ, and TNF-α in OSA versus control subjects. Following 8 weeks of treatment, continuous positive airway pressure downregulated TLR2 and TLR4 expression and abrogated the release of inflammatory cytokines.

Conclusion

OSA is associated with enhanced expression and signaling events downstream of TLR2 and TLR4 in circulating monocytes. These observations are mitigated by CPAP therapy, which suggest that TLR2 and TLR4 activation may be involved as a signaling mechanism in immune-mediated progression of atherosclerosis in OSA.

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References

  1. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP (2010) Pathophysiology of sleep apnea. Physiol Rev 90(1):47–112

    Article  PubMed  CAS  Google Scholar 

  2. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S (1993) The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 328(17):1230–1235

    Article  PubMed  CAS  Google Scholar 

  3. Redline S, Kump K, Tishler PV, Browner I, Ferrette V (1994) Gender differences in sleep disordered breathing in a community-based sample. Am J Respir Crit Care Med 149(3 Pt 1):722–726

    Article  PubMed  CAS  Google Scholar 

  4. Strohl KP, Redline S (1996) Recognition of obstructive sleep apnea. Am J Respir Crit Care Med 154(2 Pt 1):279–289

    Article  PubMed  CAS  Google Scholar 

  5. Shah NA, Yaggi HK, Concato J, Mohsenin V (2010) Obstructive sleep apnea as a risk factor for coronary events or cardiovascular death. Sleep Breath 14(2):131–136

    Article  PubMed  Google Scholar 

  6. Levy P, Tamisier R, Minville C, Launois S, Pepin JL (2011) Sleep apnoea syndrome in 2011: current concepts and future directions. Eur Respir Rev Off J Eur Respir Soc 20(121):134–146

    Article  CAS  Google Scholar 

  7. Li H, Sun B (2007) Toll-like receptor 4 in atherosclerosis. J Cell Mol Med 11(1):88–95

    Article  PubMed  CAS  Google Scholar 

  8. Mullick AE, Tobias PS, Curtiss LK (2006) Toll-like receptors and atherosclerosis: key contributors in disease and health? Immunol Res 34(3):193–209. doi:10.1385/IR:34:3:193

    Article  PubMed  CAS  Google Scholar 

  9. Michelsen KS, Doherty TM, Shah PK, Arditi M (2004) TLR signaling: an emerging bridge from innate immunity to atherogenesis. J Immunol 173(10):5901–5907

    PubMed  CAS  Google Scholar 

  10. Takeda K, Akira S (2001) Roles of Toll-like receptors in innate immune responses. Genes Cells Devoted Mol Cell Mech 6(9):733–742

    Article  CAS  Google Scholar 

  11. Stoll LL, Denning GM, Weintraub NL (2006) Endotoxin, TLR4 signaling and vascular inflammation: potential therapeutic targets in cardiovascular disease. Curr Pharm Des 12(32):4229–4245

    Article  PubMed  CAS  Google Scholar 

  12. Methe H, Kim JO, Kofler S, Weis M, Nabauer M, Koglin J (2005) Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation 111(20):2654–2661

    Article  PubMed  CAS  Google Scholar 

  13. den Dekker WK, Cheng C, Pasterkamp G, Duckers HJ (2010) Toll like receptor 4 in atherosclerosis and plaque destabilization. Atherosclerosis 209(2):314–320

    Article  Google Scholar 

  14. Michelsen KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM, Akira S, Rajavashisth TB, Arditi M (2004) Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci USA 101(29):10679–10684

    Article  PubMed  CAS  Google Scholar 

  15. Liu X, Ukai T, Yumoto H, Davey M, Goswami S, Gibson FC 3rd, Genco CA (2008) Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids. Atherosclerosis 196(1):146–154

    Article  PubMed  CAS  Google Scholar 

  16. Mullick AE, Tobias PS, Curtiss LK (2005) Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest 115(11):3149–3156

    Article  PubMed  CAS  Google Scholar 

  17. Bjorkbacka H, Kunjathoor VV, Moore KJ, Koehn S, Ordija CM, Lee MA, Means T, Halmen K, Luster AD, Golenbock DT, Freeman MW (2004) Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 10(4):416–421

    Article  PubMed  Google Scholar 

  18. Dyugovskaya L, Lavie P, Lavie L (2002) Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 165(7):934–939

    Article  PubMed  Google Scholar 

  19. Dyugovskaya L, Lavie P, Lavie L (2003) Phenotypic and functional characterization of blood gammadelta T cells in sleep apnea. Am J Respir Crit Care Med 168(2):242–249

    Article  PubMed  Google Scholar 

  20. Akinnusi ME, Paasch LL, Szarpa KR, Wallace PK, El Solh AA (2009) Impact of nasal continuous positive airway pressure therapy on markers of platelet activation in patients with obstructive sleep apnea. Respiration 77(1):25–31

    Article  PubMed  Google Scholar 

  21. Guasti L, Marino F, Cosentino M, Maroni L, Maresca AM, Colombo F, Maio RC, Castiglioni L, Saporiti F, Loraschi A, Gaudio G, Bernasconi A, Laurita E, Grandi AM, Venco A (2011) Cytokine production from peripheral blood mononuclear cells and polymorphonuclear leukocytes in patients studied for suspected obstructive sleep apnea. Sleep Breath 15(1):3–11

    Article  PubMed  Google Scholar 

  22. Akinnusi ME, Laporta R, El-Solh AA (2011) Lectin-like oxidized low-density lipoprotein receptor-1 modulates endothelial apoptosis in obstructive sleep apnea. Chest 140(6):1503–1510

    Article  PubMed  CAS  Google Scholar 

  23. Kushida CA, Chediak A, Berry RB, Brown LK, Gozal D, Iber C, Parthasarathy S, Quan SF, Rowley JA (2008) Clinical guidelines for the manual titration of positive airway pressure in patients with obstructive sleep apnea. J Clin Sleep Med 4(2):157–171

    PubMed  Google Scholar 

  24. Rechtschaffen AKA (ed) (1968) A manual of standardized terminology, techniques and scoring system of sleep stages of human subjects. US Government Printing Office, Washington, DC

    Google Scholar 

  25. Kribbs NB, Pack AI, Kline LR, Smith PL, Schwartz AR, Schubert NM, Redline S, Henry JN, Getsy JE, Dinges DF (1993) Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 147(4):887–895

    Article  PubMed  CAS  Google Scholar 

  26. Xu J, Wu Y, He L, Yang Y, Moore SA, Hsu CY (1997) Regulation of cytokine-induced iNOS expression by a hairpin oligonucleotide in murine cerebral endothelial cells. Biochem Biophys Res Commun 235(2):394–397

    Article  PubMed  CAS  Google Scholar 

  27. Dyugovskaya L, Lavie P, Hirsh M, Lavie L (2005) Activated CD8+ T-lymphocytes in obstructive sleep apnoea. Eur Respir J 25(5):820–828

    Article  PubMed  CAS  Google Scholar 

  28. Constantinidis J, Ereliadis S, Angouridakis N, Konstantinidis I, Vital V, Angouridaki C (2008) Cytokine changes after surgical treatment of obstructive sleep apnoea syndrome. Eur Arch Otorhinolaryngol 265(10):1275–1279

    Article  PubMed  Google Scholar 

  29. Lavie L (2003) Obstructive sleep apnoea syndrome—an oxidative stress disorder. Sleep Med Rev 7(1):35–51

    Article  PubMed  Google Scholar 

  30. Quercioli A, Mach F, Montecucco F (2010) Inflammation accelerates atherosclerotic processes in obstructive sleep apnea syndrome (OSAS). Sleep Breath 14(3):261–269

    Article  PubMed  Google Scholar 

  31. Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, Lee JY (2010) Hypoxic stress up-regulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor. Immunology 129(4):516–524

    Article  PubMed  CAS  Google Scholar 

  32. Kuhlicke J, Frick JS, Morote-Garcia JC, Rosenberger P, Eltzschig HK (2007) Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia. PLoS One 2(12):e1364

    Article  PubMed  Google Scholar 

  33. Frantz S, Kobzik L, Kim YD, Fukazawa R, Medzhitov R, Lee RT, Kelly RA (1999) Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 104(3):271–280

    Article  PubMed  CAS  Google Scholar 

  34. Frantz S, Kelly RA, Bourcier T (2001) Role of TLR-2 in the activation of nuclear factor kappaB by oxidative stress in cardiac myocytes. J Biol Chem 276(7):5197–5203

    Article  PubMed  CAS  Google Scholar 

  35. Selejan S, Poss J, Walter F, Hohl M, Kaiser R, Kazakov A, Bohm M, Link A (2012) Ischaemia-induced up-regulation of Toll-like receptor 2 in circulating monocytes in cardiogenic shock. Eur Heart J 33(9):1085–1094

    Article  PubMed  CAS  Google Scholar 

  36. Shalhoub J, Falck-Hansen MA, Davies AH, Monaco C (2011) Innate immunity and monocyte-macrophage activation in atherosclerosis. J Inflamm (Lond) 8:9

    Article  CAS  Google Scholar 

  37. Kuwahata S, Fujita S, Orihara K, Hamasaki S, Oba R, Hirai H, Nagata K, Ishida S, Kataoka T, Oketani N, Ichiki H, Iriki Y, Saihara K, Okui H, Ninomiya Y, Tei C (2010) High expression level of Toll-like receptor 2 on monocytes is an important risk factor for arteriosclerotic disease. Atherosclerosis 209(1):248–254

    Article  PubMed  CAS  Google Scholar 

  38. Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M (2003) Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 107(8):1129–1134

    Article  PubMed  CAS  Google Scholar 

  39. Teramoto S, Yamamoto H, Ouchi Y (2003) Increased C-reactive protein and increased plasma interleukin-6 may synergistically affect the progression of coronary atherosclerosis in obstructive sleep apnea syndrome. Circulation 107(5):E40–40

    Article  PubMed  CAS  Google Scholar 

  40. Faure E, Thomas L, Xu H, Medvedev A, Equils O, Arditi M (2001) Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol 166(3):2018–2024

    PubMed  CAS  Google Scholar 

  41. Hadley JS, Wang JE, Foster SJ, Thiemermann C, Hinds CJ (2005) Peptidoglycan of Staphylococcus aureus upregulates monocyte expression of CD14, Toll-like receptor 2 (TLR2), and TLR4 in human blood: possible implications for priming of lipopolysaccharide signaling. Infect Immun 73(11):7613–7619

    Article  PubMed  CAS  Google Scholar 

  42. Brand K, Page S, Walli AK, Neumeier D, Baeuerle PA (1997) Role of nuclear factor-kappa B in atherogenesis. Exp Physiol 82(2):297–304

    PubMed  CAS  Google Scholar 

  43. Zhai Y, Shen XD, O’Connell R, Gao F, Lassman C, Busuttil RW, Cheng G, Kupiec-Weglinski JW (2004) Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J Immunol 173(12):7115–7119

    PubMed  CAS  Google Scholar 

  44. Wu HS, Zhang JX, Wang L, Tian Y, Wang H, Rotstein O (2004) Toll-like receptor 4 involvement in hepatic ischemia/reperfusion injury in mice. Hepatobiliary Pancreat Dis Int: HBPD INT 3(2):250–253

    PubMed  CAS  Google Scholar 

  45. Lavie L, Dyugovskaya L, Golan-Shany O, Lavie P (2010) Heat-shock protein 70: expression in monocytes of patients with sleep apnoea and association with oxidative stress and tumour necrosis factor-alpha. J Sleep Res 19(1 Pt 2):139–147

    Article  PubMed  Google Scholar 

  46. Wu KM, Lin CC, Chiu CH, Liaw SF (2010) Effect of treatment by nasal continuous positive airway pressure on serum high mobility group box-1 protein in obstructive sleep apnea. Chest 137(2):303–309

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the American Academy of Sleep Medicine Physician-Scientist Training Award grant (MEA).

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Authors and Affiliations

  1. The Veterans Affairs Western New York Healthcare System, Medical Research, Bldg. 20 (151) VISN02, 3495 Bailey Avenue, 14215-1199, Buffalo, NY, USA

    Morohunfolu Akinnusi, Thomas Kufel & Ali A. El-Solh

  2. Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Western New York Respiratory Research Center, Buffalo, NY, USA

    Morohunfolu Akinnusi, Philippe Jaoude, Thomas Kufel & Ali A. El-Solh

  3. Department of Social and Preventive Medicine, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY, USA

    Ali A. El-Solh

  4. School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA

    Ali A. El-Solh

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  1. Morohunfolu Akinnusi
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  2. Philippe Jaoude
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  4. Ali A. El-Solh
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Correspondence to Ali A. El-Solh.

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Akinnusi, M., Jaoude, P., Kufel, T. et al. Toll-like receptor activity in patients with obstructive sleep apnea. Sleep Breath 17, 1009–1016 (2013). https://doi.org/10.1007/s11325-012-0791-2

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  • DOI: https://doi.org/10.1007/s11325-012-0791-2

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