Hypoxia and Cigarette Smoke - A Combined Threat to the Brain: Role of Toll-like Receptor 4 in Neuroinflammatory Changes
Abstract
The mammalian brain is composed of 20% of oxygen. The depletion in the level of oxygen may lead to hypoxia, resulting in neurological changes. Recent findings of Toll-like receptors (TLR) such as TLR-2, 3, 4 and 8 in the mammalian nervous system showed neuroinflammation in the brain. The activation of TLR4 by both exogenous and endogenous ligands leads to various inflammatory diseases like atherosclerosis, Crohn’s disease, ulcerative colitis, rheumatoid arthritis and prostate cancer. This study confirms the involvement of NF-κB in TLR4-axisinduced neuroinflammationin the brain. Cigarette Smoke contains many toxic chemicals such as carcinogenic compounds which are injurious to health, causing death worldwide. The role of TLR4 in activating the Brain during Cigarette Smoke exposure is not yet understood. Hence this study reviewed the use of the cell culture in vitro model as well as in vivo mouse model of TLR4-/- mouse exposed to hypobaric hypoxia
to test hypothesis.
How to cite this article:
Krishnan J, Farhat SK, Anbalagan R. Hypoxia and Cigarette Smoke - A Combined Threat to the Brain: Role of Toll-like Receptor 4 in Neuroinflammatory Changes. J Commun Dis. 2022;54(3):67-74.
DOI: https://doi.org/10.24321/0019.5138.202291
References
Shukitt-Hale B, Stillman MJ, Lieberman HR. Tyrosine administration prevents hypoxia-induced decrements
in learning and memory. Physiol Behav. 1996 Apr-May;59(4-5):867-71.[PubMed] [Google Scholar]
Goto H, Rylander R. Kinetics of inhaled lipopolysaccharide in the guinea pig. J Lab Clin Med. 1987 Sep;110(3):287-91. [PubMed] [Google Scholar]
Takeda K. Kaisho T and Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335-76.
Liu JT, Lee IH, Wang CH, Chen KC, Lee CI, Yang YK. Cigarette smoking might impair memory and sleep
quality. J Formos Med Assoc. 2013 May;112(5):287-90. [PubMed] [Google Scholar]
Gorina R, Font-Nieves M, Márquez-Kisinousky L, Santalucia T, Planas AM. Astrocyte TLR4 activation
induces a proinflammatory environment through the interplay between MyD88-dependent NFκB
signaling, MAPK and Jak1/Stat1 pathways. Glia. 2011 Feb;59(2):242-55. [PubMed] [Google Scholar]
Moylan S, Jacka FN, Pasco JA, Berk M. How cigarette smoking may increase the risk of anxiety symptoms
and anxiety disorders: A critical review of biological pathways. Brain Behav. 2013 May;3(3):302-26.
[PubMed] [Google Scholar]
MartÃnez-Cerdeño V, Noctor SC. Neural progenitor cell terminology. Front Neuroanat. 2018 Dec;12:104.
[PubMed] [Google Scholar]
Khanna A, Guo M, Mehra M, Royal W 3rd. Inflammation and oxidative stress induced by cigarette smoke in
Lewis rat brains. J Neuroimmunol. 2013 Jan;254(1-2):69-75.[PubMed] [Google Scholar]
Molteni M, Gemma S, Rossetti C. The role of toll-like receptor 4 in infectious and noninfectious inflammation.
Mediators Inflamm. 2016;2016:6978936.[PubMed] [Google Scholar]
Krishnan J, Selvarajoo K, Tsuchiya M, Lee G, Choi S. Toll-like receptor signal transduction. Exp Mol Med.
Aug;39(4):421-38.[PubMed] [Google Scholar]
Watson MB, Costello DA, Carney DG, McQuillan K, Lynch MA. SIGIRR modulates the inflammatory response in
the brain. Brain Behav Immun. 2010 Aug;24(6):985-95. [PubMed] [Google Scholar]
Watson SA, McStay GP. Functions of Cytochrome c oxidase assembly factors. Int J Mol Sci. 2020
Sep;21(19):7254.[PubMed] [Google Scholar]
Zhu HT, Bian C, Yuan JC, Chu WH, Xiang X, Chen F, Wang CS, Feng H, Lin JK.Curcumin attenuates acute
inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic
brain injury. J Neuroinflammation. 2014 Mar;11:59. [PubMed] [Google Scholar]
Manickam M, Tulsawani R. Survival response of hippocampal neurons under low oxygen conditions
induced by Hippophae rhamnoides is associated with JAK/STAT signaling. PLoS One. 2014 Feb;9(2):e87694.
[PubMed] [Google Scholar]
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006 Feb;124(4):783-801.
[PubMed] [Google Scholar]
Keith CR, Thomann RV. Aerosol studies of cigarette smoke. Environ Sci Technol.1989;23:413-7.
Genbacev-Krtolica O. Highlight for phenols, quinolines, indoles, benzene and 2-cyclopenten-1-ones are
oviduct toxicants in cigarette smoke, by Prue Talbot, Karen Riveles and Ryan Rosa: List of tobacco-smoke
constituents that are harmful for reproduction grows - Passive smoke. Toxicol Sci. 2005 Jul;86(1):4-5.[PubMed]
[Google Scholar]
Pryor WA, Prier DG, Church DF. Electron-spin resonance study of mainstream and sidestream cigarette smoke: Nature of the free radicals in gas-phase smoke and in cigarette tar. Environ Health Perspect. 1983 Jan;47:345-55. [PubMed] [Google Scholar]
Moriarty SE, Shah JH, Lynn M, Jiang S, Openo K, Jones DP, Sternberg P. Oxidation of glutathione and cysteine
in human plasma associated with smoking. Free Radic Biol Med. 2003 Dec;35(12):1582-8. [PubMed] [Google
Scholar]
Mathers CD, Loncar D.Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med.
Nov;3(11):e442. [PubMed] [Google Scholar]
Olsson B, Bondesson E, Borgström L, Edsbäcker S, Eirefelt S, Ekelund K, Gustavsson L, Hegelund-Myrbäck
T. Pulmonary drug metabolism, clearance and absorption. InControlled pulmonary drug delivery 2011
(pp. 21-50). Springer, New York, NY. [Google Scholar]
Van der Toorn M, Smit-de Vries MP, Slebos DJ, de Bruin HG, Abello N, van Oosterhout AJ, Bischoff R,
Kauffman HF. Cigarette smoke irreversibly modifies glutathione in airway epithelial cells. Am J Physiol Lung
Cell Mol Physiol. 2007 Nov;293(5):L1156-62.[PubMed] [Google Scholar]
Luppi, F., Aarbiou, J., van Wetering, S., Rahman, I., de Boer, W. I., Rabe, K. F., & Hiemstra, P. S. (2005). Effects
of cigarette smoke condensate on proliferation and wound closure of bronchial epithelial cells in vitro:
Role of glutathione. Respiratory Research, 6. [PubMed] [Google Scholar]
Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest. 2012
Apr;122(4):1164-71.[PubMed] [Google Scholar]
Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity.
Immunity. 2011 May;34(5):637-50. [PubMed] [Google Scholar]
Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J, Chow JC, Strauss JF 3rd.The extra domain
A of fibronectin activates toll-like receptor 4. J Biol Chem. 2001 Mar;276(13):10229-33.[PubMed] [Google
Scholar]
Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer
RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, Noble PW. Regulation of lung injury and repair by
Toll-like receptors and hyaluronan. Nat Med. 2005 Nov;11(11):1173-9. [PubMed] [Google Scholar]
Khanna AK, Xu J, Uber PA, Burke AP, Baquet C, Mehra MR.Tobacco smoke exposure in either the donor or
recipient before transplantation accelerates cardiac allograft rejection, vascular inflammation and graft
loss. Circulation. 2009 Nov;120(18):1814-21. [PubMed] [Google Scholar]
Bulut Y, Faure E, Thomas L, Karahashi H, Michelsen KS, Equils O, Morrison SG, Morrison RP, Arditi M. Chlamydial heat shock protein 60 activates macrophages and endothelial cells through toll-like receptor 4 and MD2 in a MyD88-Dependent Pathway. J Immunol. 2002 Feb;168(3):1435-40.[PubMed] [Google Scholar]
Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA, Walsh EE, Freeman MW, Golenbock DT
anderson LJ, Finberg RW. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory
syncytial virus. Nat Immunol. 2000 Nov;1(5):398-401.[PubMed] [Google Scholar]
Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat
Immunol. 2001 Aug;2(8):675-80.[PubMed] [Google Scholar]
Horie Y, Meguro A, Ota M, Kitaichi N, Katsuyama Y, Takemoto Y, Namba K, Yoshida K, Song YW, Park
KS, Lee EB, Inoko H, Mizuki N, Ohno S. Association of TLR4 polymorphisms with Behçet’s disease in a
Korean population. Rheumatology (Oxford). 2009 Jun;48(6):638-42. [PubMed] [Google Scholar]
Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA. TLR4 mutations
are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000 Jun;25(2):187-91. [PubMed]
[Google Scholar]
Schoch CL, Seifert KA, Huhndorf S, Robert V, Spouge JL, Levesque CA, Chen W; Fungal Barcoding Consortium;
Fungal Barcoding Consortium Author List. Nuclear ribosomal internal transcribed spacer (ITS) region as
a universal DNA barcode marker for Fungi. Proc Natl Acad Sci U S A. 2012 Apr;109(16):6241-6.[PubMed]
[Google Scholar]
Schmitt C, Humeny A, Becker CM, Brune K, Pahl A. Polymorphisms of TLR4: Rapid genotyping and reduced
response to lipopolysaccharide of TLR4 mutant alleles. Clin Chem. 2002 Oct;48(10):1661-7.[PubMed] [Google
Scholar]
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F. Focal glial
activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I]
transgenic mice.J Neuroinflammation. 2005 Oct;2:22. [PubMed] [Google Scholar]
Zhao M, Zhou A, Xu L, Zhang X. The role of TLR4-mediated PTEN/PI3K/AKT/NF-κB signaling pathway
in neuroinflammation in hippocampal neurons. Neuroscience. 2014 Jun;269:93-101. [PubMed] [Google
Scholar]
Suzuki Y, Hattori K, Hamanaka J, Murase T, Egashira Y, Mishiro K, Ishiguro M, Tsuruma K, Hirose Y, Tanaka
H, Yoshimura S, Shimazawa M, Inagaki N, Nagasawa H, Iwama T, Hara H. Pharmacological inhibition of
TLR4-NOX4 signal protects against neuronal death in transient focal ischemia. Sci Rep. 2012;2:896. [PubMed]
[Google Scholar]
Vega-Avelaira D, Géranton SM, Fitzgerald M. Differential regulation of immune responses and macrophage/
neuron interactions in the dorsal root ganglion in young and adult rats following nerve injury. Mol Pain. 2009
Dec;5:70.[PubMed] [Google Scholar]
Qi J, Buzas K, Fan H, Cohen JI, Wang K, Mont E, Klinman D, Oppenheim JJ, Howard OM. Painful pathways
induced by TLR stimulation of dorsal root ganglion neurons. J Immunol. 2011 Jun;186(11):6417-26.
[PubMed] [Google Scholar]
Alfonso-Loeches S, Pascual-Lucas M, Blanco AM, Sanchez-Vera I, Guerri C. Pivotal role of TLR4
receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci. 2010 Jun;30(24):8285-95.
[PubMed] [Google Scholar]
Pascual M, Baliño P, Alfonso-Loeches S, Aragón CM, Guerri C. Impact of TLR4 on behavioral and cognitive
dysfunctions associated with alcohol-induced neuroinflammatory damage. Brain Behav Immun.
Jun;25 Suppl 1:S80-91. [PubMed] [Google Scholar]
Hedström AK, Hillert J, Olsson T, Alfredsson L. Smoking and multiple sclerosis susceptibility. Eur J Epidemiol.
Nov;28(11):867-74. [PubMed] [Google Scholar]
Naik P, Fofaria N, Prasad S, Sajja RK, Weksler B, Couraud PO, Romero IA, Cucullo L. Oxidative and proinflammatory impact of regular and denicotinized cigarettes on blood brain barrier endothelial cells: is
smoking reduced or nicotine-free products really safe? BMC Neurosci. 2014 Apr;15:51.[PubMed] [Google
Scholar]
Hasday JD, Bascom R, Costa JJ, Fitzgerald T, Dubin W. Bacterial endotoxin is an active component of cigarette
smoke. Chest. 1999 Mar;115(3):829-35. [PubMed] [Google Scholar]
Kühn S, Schubert F, Gallinat J. Reduced thickness of medial orbitofrontal cortex in smokers. Biol Psychiatry.
Dec;68(11):1061-5. [PubMed] [Google Scholar]
Gallinat J, Meisenzahl E, Jacobsen LK, Kalus P, Bierbrauer J, Kienast T, Witthaus H, Leopold K, Seifert F, Schubert F, Staedtgen M. Smoking and structural brain deficits: a volumetric MR investigation. Eur J Neurosci. 2006 Sep;24(6):1744-50.[PubMed] [Google Scholar]
Vaglenova J, Parameshwaran K, Suppiramaniam V, Breese CR, Pandiella N, Birru S. Long-lasting teratogenic
effects of nicotine on cognition: gender specificity and role of AMPA receptor function. Neurobiol Learn Mem.
Oct;90(3):527-36. [PubMed] [Google Scholar]
Ochoa EL, Li L, McNamee MG. Desensitization of central cholinergic mechanisms and neuroadaptation to
nicotine. Mol Neurobiol. 1990 Fall-Winter;4(3-4):251-87. [PubMed] [Google Scholar]
Léna C, Changeux JP, Mulle C. Evidence for “preterminal†nicotinic receptors on GABAergic axons
in the rat interpeduncular nucleus. J Neurosci. 1993 Jun;13(6):2680-8. [PubMed] [Google Scholar]
Henningfield JE, Cohen CA, Pickworth WB. Psychopharmacology of nicotine. Nicotine addiction:
Principles and management. 1993:24-45. [Google Scholar]
Corley J, Gow AJ, Starr JM, Deary IJ. Smoking, childhood IQ and cognitive function in old age. J Psychosom Res.
Aug;73(2):132-8. [PubMed] [Google Scholar]
Barnes PJ. New molecular targets for the treatment of neutrophilic diseases. J Allergy Clin Immunol. 2007
May;119(5):1055-62; quiz 1063-4. [PubMed] [Google Scholar]
Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet
Neurol. 2011 Sep;10(9):819-28.[PubMed] [Google Scholar]
Brody AL, Mandelkern MA, Jarvik ME, Lee GS, Smith EC, Huang JC, Bota RG, Bartzokis G, London ED. Differences between smokers and nonsmokers in regional gray matter volumes and densities. Biol Psychiatry. 2004 Jan;55(1):77-84. [PubMed] [Google Scholar]
Almeida OP, Garrido GJ, Lautenschlager NT, Hulse GK, Jamrozik K, Flicker L. Smoking is associated with
reduced cortical regional gray matter density in brain regions associated with incipient Alzheimer disease.
Am J Geriatr Psychiatry. 2008 Jan;16(1):92-8. [PubMed] [Google Scholar]
Durazzo TC, Mon A, Gazdzinski S, Meyerhoff DJ. Chronic cigarette smoking in alcohol dependence: associations with cortical thickness and N-acetylaspartate levels in the extended brain reward system. Addict Biol. 2013 Mar;18(2):379-91.[PubMed] [Google Scholar]
Durazzo TC, Cardenas VA, Studholme C, Weiner MW, Meyerhoff DJ. Non-treatment-seeking heavy drinkers:
effects of chronic cigarette smoking on brain structure. Drug Alcohol Depend. 2007 Feb;87(1):76-82. [PubMed]
[Google Scholar]
Durazzo TC, Insel PS, Weiner MW; Alzheimer Disease Neuroimaging Initiative. Greater regional brain atrophy
rate in healthy elderly subjects with a history of cigarette smoking. Alzheimers Dement. 2012 Nov;8(6):513-9.
[PubMed] [Google Scholar]
Akiyama H, Meyer JS, Mortel KF, Terayama Y, Thornby JI, Konno S. Normal human aging: factors contributing
to cerebral atrophy. J Neurol Sci. 1997 Nov;152(1):39-49.[PubMed] [Google Scholar]
Pierik M, Vermeire S, El-Housni H, Claessens G, Quertinmont E, Joosens S, Van Gossum A, Deviere J,
Rutgeerts P, Franchimont D. Toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with ulcerative
colitis (UC) 0. Gastroenterology. 2003;4(124):A370. [Google Scholar]
Zarei M, Ibarretxe-Bilbao N, Compta Y, Hough M, Junque C, Bargallo N, Tolosa E, Martà MJ. Cortical
thinning is associated with disease stages and dementia in Parkinson’s disease. J Neurol Neurosurg Psychiatry.
Aug;84(8):875-81.[PubMed] [Google Scholar]
Miller GJ, Bauer KA, Cooper JA, Rosenberg RD. Activation of the coagulant pathway in cigarette smokers. Thromb Haemost. 1998 Mar;79(3):549-53. [PubMed] [Google Scholar]
Satoto TBT, Satrisno H, Lazuardi L, Diptyanusa A, Purwaningsih, Rumbiwati, Kuswati. Insecticide
resistance in Aedes aegypti: An impact from human urbanization? PLoS One. 2019 Jun 24;14(6):e0218079.
[PubMed] [Google Scholar]
Rahman SM, Hossain SM. Dengue prevention and control: Bangladesh context: Dengue Bangladesh
Context. Bangladesh Med Res Counc Bull. 2019 Aug;45(2):66-7. [Google Scholar]
Chan A, Chiang LP, Hapuarachchi HC, Tan CH, Pang SC, Lee R, Lee KS, Ng LC, Lam-Phua SG. DNA barcoding:
complementing morphological identification of mosquito species in Singapore. Parasit Vectors. 2014
Dec;7:569.[PubMed] [Google Scholar]
Shah RS, Cole JW. Smoking and stroke: the more you smoke the more you stroke. Expert Rev Cardiovasc
Ther. 2010 Jul;8(7):917-32.[PubMed] [Google Scholar]
Harman SM, Liang L, Tsitouras PD, Gucciardo F, Heward CB, Reaven PD, Ping W, Ahmed A, Cutler
RG. Urinary excretion of three nucleic acid oxidation adducts and isoprostane F(2)alpha measured by liquid
chromatography-mass spectrometry in smokers, ex-smokers and nonsmokers.Free Radic Biol Med. 2003
Nov;35(10):1301-9. [PubMed] [Google Scholar]
Chang RC, Ho YS, Wong S, Gentleman SM, Ng HK. Neuropathology of cigarette smoking. Acta
Neuropathol. 2014 Jan;127(1):53-69.[PubMed] [Google Scholar]
Chen H, Cowan MJ, Hasday JD, Vogel SN, Medvedev AE. Tobacco smoking inhibits expression of
proinflammatory cytokines and activation of IL-1Rassociated kinase, p38 and NF-kappaB in alveolar
macrophages stimulated with TLR2 and TLR4 agonists. J Immunol. 2007 Nov;179(9):6097-106. [PubMed]
[Google Scholar]
Michie HR, Manogue KR, Spriggs DR, Revhaug A, O’Dwyer S, Dinarello CA, Cerami A, Wolff SM, Wilmore
DW. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988
Jun;318(23):1481-6.[PubMed] [Google Scholar]
Larsson L, Szponar B, Pehrson C. Tobacco smoking increases dramatically air concentrations of endotoxin.
Indoor Air. 2004 Dec;14(6):421-4. [PubMed] [Google Scholar]
Hines DJ, Choi HB, Hines RM, Phillips AG, MacVicar BA. Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides. PLoS One. 2013;8(3):e60388.
[PubMed] [Google Scholar]
Leow-Dyke S, Allen C, Denes A, Nilsson O, Maysami S, Bowie AG, Rothwell NJ, Pinteaux E. Neuronal Toll-like receptor 4 signaling induces brain endothelial activation and neutrophil transmigration in vitro. J Neuroinflammation. 2012 Oct;9:230. [PubMed] [Google Scholar]
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