Neuroinflamación mediada por los astrocitos en el envejecimiento y la neurodegeneración a través del factor nuclear ϰβ y el receptor de hidrocarburos de arilo

Mónica Adriana Torres-Ramos, Brian Iván Morales-López

Resumen


Durante el envejecimiento existe un aumento en la expresión de las proteínas asociadas con la inflamación en el sistema nervioso central (SNC). Se sabe que, con el avance de la edad, los astrocitos promueven la neuroinflamación crónica que favorece la pérdida de la homeostasis y predispone a la muerte neuronal, estas células gliales pueden responder a los estímulos inflamatorios a través de diferentes cascadas de señalización que involucran a dos importantes factores de transcripción, el factor nuclear ϰβ (NFϰβ) y el receptor de hidrocarburos de arilo (AHR). El NFϰβ es rápidamente inducible, tiene un papel vasto en la inducción de genes proinflamatorios como citocinas y quimiocinas. El AHR pertenece a una familia de receptores vinculada a la vascularización, el metabolismo y con la protección de los efectos tóxicos provocados por hidrocarburos aromáticos halogenados y los hidrocarburos aromáticos policíclicos; se asocia a la respuesta inflamatoria sistémica y se ha descrito como un regulador negativo de la inflamación mediada por NFϰβ. El conocimiento de los mecanismos moleculares implicados en la respuesta inflamatoria de los astrocitos ayuda a un mejor entendimiento del proceso de envejecimiento y de la neurodegeneración, así como en la búsqueda de mediadores inflamatorios como dianas terapéuticas para enfermedades asociadas con el avance de la edad.

Abstract

During aging, there is an increase in the expression of proteins associated with inflammation in the Central Nervous System (CNS). It is known that, with advancing age, astrocytes promote chronic neuroinflammation that favors loss of homeostasis and predisposes to neuronal death. These glial cells can respond to inflammatory stimuli through signaling cascades involving two essential transcription factors, Nuclear Factor ϰβ (NFϰβ) and Aryl Hydrocarbon Receptor (AHR). NFϰβ is rapidly inducible; it has a significant role in the induction of proinflammatory genes such as cytokines and chemokines. The AHR belongs to a family of receptors linked to vascularization, metabolism, and protection from the toxic effects caused by halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons; it is associated with the systemic inflammatory response and has been described as a negative regulator of NFϰβ -mediated inflammation. Knowing the molecular mechanisms involved in astrocytes' inflammatory response helps to understand better the aging process and neurodegeneration, as well as the search for inflammatory mediators as therapeutic targets for associated diseases.

Keywords: AHR; NFϰβ; senescence; neuroinflammation; gut microbiota.


Palabras clave


AHR; NFϰβ; senescencia; neuroinflamación; microbiota intestinal.

Texto completo:

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Referencias


Organizacion Mundial de la Salud (OMS) “Envejecimiento” https://www.who.int/es/health-topics/ageing#tab=tab_1

Pizza V, Agresta A, W. D’Acunto C, Festa M, Capasso A. Neuroinflamm-Aging and Neurodegenerative Diseases: An Overview. CNS Neurol Disord - Drug Targets. 2012;10(5). doi:10.2174/187152711796235014

Møller P, Løhr M, Folkmann JK, Mikkelsen L, Loft S. Aging and oxidatively damaged nuclear DNA in animal organs. Free Radic Biol Med. 2010;48(10). doi:10.1016/j.freeradbiomed.2010.02.003

Poon HF, Calabrese V, Scapagnini G, Butterfield DA. Free radicals and brain aging. Clin Geriatr Med. 2004;20(2). doi:10.1016/j.cger.2004.02.005

Torres-Ramos MA, Campos-Esparza MR. Daño en el Sistema Nervioso y Estrés Oxidativo: Antioxidantes. En: “Estrés Oxidativo y antioxidantes celulares”. Coordinador: Fernando Jaramillo Juárez. Ediciones: Textos Universitarios. Universidad de Aguas Calientes. Published online 2012:2012.

Foster TC. Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell. 2007;6(3). doi:10.1111/j.1474-9726.2007.00283.x

Navarro A, Boveris A. Brain mitochondrial dysfunction in aging, neurodegeneration, and Parkinson’s disease. Front Aging Neurosci. 2010;2(SEP). doi:10.3389/fnagi.2010.00034

Sulzer D, Mosharov E, Talloczy Z, Zucca FA, Simon JD, Zecca L. Neuronal pigmented autophagic vacuoles: Lipofuscin, neuromelanin, and ceroid as macroautophagic responses during aging and disease. J Neurochem. 2008;106(1). doi:10.1111/j.1471-4159.2008.05385.x

Cannizzo ES, Clement CC, Sahu R, Follo C, Santambrogio L. Oxidative stress, inflamm-aging and immunosenescence. J Proteomics. 2011;74(11). doi:10.1016/j.jprot.2011.06.005

Bhat R, Crowe EP, Bitto A. Astrocyte Senescence as a Component of Alzheimer’s Disease. PLoS One. 2012;7(9). doi:10.1371/journal.pone.0045069.

Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O. Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 2009 412. 2009;4(12):1798-1806. doi:10.1038/nprot.2009.191

Zhou R, Han L, Li G, Tong T. Senescence delay and repression of p16INK4a by Lsh via recruitment of histone deacetylases in human diploid fibroblasts. Nucleic Acids Res. 2009;37(15). doi:10.1093/nar/gkp533

Funayama R, Ishikawa F. Cellular senescence and chromatin structure. Chromosoma. 2007;116(5). doi:10.1007/s00412-007-0115-7

Aksoy O, Chicas A, Zeng T, Zhao Z, McCurrach M, Wang X, Lowe SW. The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence. Genes Dev. 2012;26(14). doi:10.1101/gad.196238.112

Qian Y, Chen X. Senescence regulation by the p53 protein family. Methods Mol Biol. 2013;965. doi:10.1007/978-1-62703-239-1_3

Salminen A, Ojala J, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H. Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci. 2011;34(1). doi:10.1111/j.1460-9568.2011.07738.x

Godbout JP, Johnson RW. Age and Neuroinflammation: A Lifetime of Psychoneuroimmune Consequences. Immunol Allergy Clin North Am. 2009;29(2). doi:10.1016/j.iac.2009.02.007

Lucin KM, Wyss-Coray T. Immune Activation in Brain Aging and Neurodegeneration: Too Much or Too Little? Neuron. 2009;64(1). doi:10.1016/j.neuron.2009.08.039

Lynch MA. Age-related neuroinflammatory changes negatively impact on neuronal function. Front Aging Neurosci. 2010;1. doi:10.3389/neuro.24.006.2009

Bitto A, Sell C, Crowe E, Lorenzini A, Malaguti M, Hrelia S, Torres C. Stress-induced senescence in human and rodent astrocytes. Exp Cell Res. 2010;316(17). doi:10.1016/j.yexcr.2010.06.021

Escartin C, Galea E, Lakatos A, O´Callaghan JP, Petzold GC, Serrano-Pozo A, Steinhäuser C, Volterra A, Carmignoto G, Agarwal A, Allen NJ, Araque A, Barbeito L, Barzilai A, Bergles DE, Bonvento G, Butt AM, Chen WT, Cohen-Salmon M, Cunningham C, Deneen B, de Strooper B, Díaz-Castro B, Farina C, Freeman M, Gallo V, Goldman JE, Goldman SA, Götz M, Gutiérrez A, Haydon PG, Heiland DH, Hol EM, Holt MG, Iino M, Kastanenka KV, Kettenmann H, Khakh BS, Koizumi S, Lee CJ, Liddelow SA, MacVicar BA, Magistretti P, Messing A, Mishra A, Molofsky AV, Murai KK, Norris CM, Okada S, Oliet SHR, Oliveira JF, Panatier A, Parpura V, Pekna M, Pekny M, Pellerin L, Perea G, Pérez-Nievas BG, Pfrieger FW, Poskanzer KE, Quintana FJ, Ransohoff RM, Riquelme-Perez M, Robel S, Rose CR, Rothstein JD, Rouach N, Rowitch DH, Semyanov A, Sirko S, Sontheimer H, Swanson RA, Vitorica J, Wanner IB, Wood LB, Wu J, Zheng B, Zimmer ER, Zorec R, Sofroniew MV, Verkhratsky A. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021;24(3). doi:10.1038/s41593-020-00783-4

Cohen J, Torres C. Astrocyte senescence: Evidence and significance. Aging Cell. 2019;18(3). doi:10.1111/ACEL.12937

Ojo JO, Rezaie P, Gabbott PL, Stewart MG. Impact of age-related neuroglial cell responses on hippocampal deterioration. Front Aging Neurosci. 2015;7(APR). doi:10.3389/fnagi.2015.00057

McGeer PL, McGeer EG. Glial Cell Reactions in Neurodegenerative Diseases Pathophysiology and Therapeutic Interventions. Alzheimer Dis Assoc Disord. 1998;12(2). doi:10.1097/00002093-199803001-00001

Lee JK, Tran T, Tansey MG. Neuroinflammation in Parkinson’s disease. J Neuroimmune Pharmacol. 2009;4(4):419-429. doi:10.1007/S11481-009-9176-0

Yankner BA, Lu T, Loerch P. The aging brain. Annu Rev Pathol Mech Dis. 2008;3:41-66. doi:10.1146/ANNUREV.PATHMECHDIS.2.010506.092044

Pertusa M, García-Matas S, Rodríguez-Farré E, Sanfeliu C, Cristòfol R. Astrocytes aged in vitro show a decreased neuroprotective capacity. J Neurochem. 2007;101(3). doi:10.1111/j.1471-4159.2006.04369.x

Vogel CFA, Khan EM, Leung PSC, Gershwin ME, Chang WLW, Wu D, Haarmann-Stemmann T, Hoffmann A, Denison M. Cross-talk between aryl hydrocarbon receptor and the inflammatory response: A role for nuclear factor-κB. J Biol Chem. 2014;289(3). doi:10.1074/jbc.M113.505578

Zhang Q, Lenardo MJ, Baltimore D. 30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology. Cell. 2017;168(1-2):37-57. doi:10.1016/J.CELL.2016.12.012

Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD. NF-κB in aging and disease. Aging Dis. 2011;2(6)

Ben-Neriah Y. Regulatory functions of ubiquitination in the immune system. Nat Immunol. 2002;3(1). doi:10.1038/ni0102-20

Karunaweera N, Raju R, Gyengesi E, Munch G. Plant polyphenols as inhibitors of nf-Кb induced cytokine production—A potential anti-inflammatory treatment for alzheimer’s disease? Front Mol Neurosci. 2015;8(June):24. doi:10.3389/FNMOL.2015.00024/BIBTEX

Attiq A, Yao LJ, Afzal S, Khan MA. The triumvirate of NF-κB, inflammation and cytokine storm in COVID-19. Int Immunopharmacol. 2021;101. doi:10.1016/j.intimp.2021.108255

Sivandzade F, Prasad S, Bhalerao A, Cucullo L. NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches. Redox Biol. 2019;21. doi:10.1016/j.redox.2018.11.017

Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler TW. When NRF2 talks, who’s listening? Antioxidants Redox Signal. 2010;13(11). doi:10.1089/ars.2010.3216

Hao N, Whitelaw ML. The emerging roles of AhR in physiology and immunity. Biochem Pharmacol. 2013;86(5). doi:10.1016/j.bcp.2013.07.004

Wang C, Xu CX, Krager SL, Bottum KM, Liao DF, Tischkau SA. Aryl hydrocarbon receptor deficiency enhances insulin sensitivity and reduces PPAR α pathway activity in mice. Environ Health Perspect. 2011;119(12). doi:10.1289/ehp.1103593

Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol. 2019;19(3). doi:10.1038/s41577-019-0125-8

Denison MS, Nagy SR. Activation of the Aryl Hydrocarbon Receptor by Structurally Diverse Exogenous and Endogenous Chemicals. Annu Rev Pharmacol Toxicol. 2003;43. doi:10.1146/annurev.pharmtox.43.100901.135828

Zhang S, Qin C, Safe SH. Flavonoids as aryl hydrocarbon receptor agonists/antagonists: Effects of structure and cell context. Environ Health Perspect. 2003;111(16). doi:10.1289/ehp.6322

Filbrandt CR, Wu Z, Zlokovic B, Opanashuk L, Gasiewicz TA. Presence and functional activity of the aryl hydrocarbon receptor in isolated murine cerebral vascular endothelial cells and astrocytes. In: NeuroToxicology. Vol 25. ; 2004. doi:10.1016/j.neuro.2003.08.007

Lee YH, Lin CH, Hsu PC, Sun YY, Huang YJ, Zhuo JH, Wang CY, Gan YL, Hung CC, Kuan CY, Shie FS. Aryl hydrocarbon receptor mediates both proinflammatory and anti-inflammatory effects in lipopolysaccharide-activated microglia. Glia. 2015;63(7). doi:10.1002/glia.22805

Karunaweera N, Raju R, Gyengesi E, Munch G. Plant polyphenols as inhibitors of nf-Кb induced cytokine production—A potential anti-inflammatory treatment for alzheimer’s disease? Front Mol Neurosci. 2015;8(June):24. doi:10.3389/FNMOL.2015.00024/BIBTEX

Rothhammer V, Mascanfroni ID, Bunse L, Takenaya MC, Kenison JE, Mayo L, Chao CC, Patel B, Yan R, Blain M, Alvarez JI, Kébir H, Anandasabapathy N, Izquierdo G, Jung S, Obholzer N, Pochet N, Clish CB, Prinz M, Prat A, Antel J, Quintana FJ. Type i interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016;22(6):586-597. doi:10.1038/nm.4106

Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner H. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453(7191):65-71. doi:10.1038/nature06880

Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008;453(7191):106-109. doi:10.1038/nature06881

Cua DJ, Tato CM. Innate IL-17-producing cells: The sentinels of the immune system. Nat Rev Immunol. 2010;10(7). doi:10.1038/nri2800

Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC, Ardura-Fabregat A, de Lima KA, Gutiérrez-Vázquez C, Hewson P, Staszewski O, Blain M, Healy L, Neziraj T, Borio M, Wheeler M, Dragin LL, Laplaud DA, Antel J, Alvarez JI, Prinz M, Quintana FJ. Microglial control of astrocytes in response to microbial metabolites. Nat 2018 5577707. 2018;557(7707):724-728. doi:10.1038/s41586-018-0119-x

Ramos-García NA, Orozco-Ibarra M, Estudillo E, Elizondo G, Apo EG, Macías LGC, Sosa-Ortíz AL, Torres-Ramos MA. Aryl hydrocarbon receptor in post-mortem hippocampus and in serum from young, elder, and alzheimer’s patients. Int J Mol Sci. 2020;21(6). doi:10.3390/ijms21061983

Barroso A, Mahler JV, Fonseca-Castro PH, Quintana FJ. The aryl hydrocarbon receptor and the gut–brain axis. Cell Mol Immunol. 2021;18(2). doi:10.1038/s41423-020-00585-5




DOI: https://doi.org/10.25009/eb.v13i32.2604

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