Rcor2 underexpression in senescent mice: a target for inflammaging?

Journal of Neuroinflammation

Perla Kaliman²  Coral Sanfeliu²  Merce Pallàs³  Rosa María Escorihuela⁴  Marcelina Párrizas²  Rosa Cristòfol¹  Marta Cosín-Tomás³  Marco Castro-Freire²  Patricia Molina-Martínez¹  María J Alvarez-López³ 

[1] Institut d’Investigacions Biomèdiques de Barcelona (IIBB), CSIC, Rosselló 161, E-08036 Barcelona, Spain;Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Rosellón 149, E-08036 Barcelona, Spain;Unidad de Farmacología y Farmacognósia. Institut de Biomedicina (IBUB), Universidad de Barcelona y CIBERNED. Facultad de Farmacia, Av Diagonal, 643, E-08028 Barcelona, Spain;Instituto de Neurociencias, Departamento de Psiquiatría y Medicina Legal. Facultad de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra, Bellaterra (Cerdanyola del Vallès), E-08193 Barcelona, Spain

关键词: IL6;    Inflammation;    SAMP8;    Aging;    RCOR2;   

Others  :  1151335
DOI  :  10.1186/1742-2094-11-126

 received in 2014-04-15, accepted in 2014-07-07,  发布年份 2014

【 摘 要 】

Background

Aging is characterized by a low-grade systemic inflammation that contributes to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD). However, little knowledge is currently available on the molecular processes leading to chronic neuroinflammation. In this context, recent studies have described the role of chromatin regulators in inflammation and longevity including the REST corepressor (Rcor)-2 factor, which seems to be involved in an inflammatory suppressive program.

Methods

To assess the impact of Rcor2 in age-related inflammation, gene expression levels were quantified in different tissues and ages of the spontaneous senescence-accelerated P8 mouse (P8) using the SAMR1 mouse (R1) as a control. Specific siRNA transfection in P8 and R1 astrocyte cultures was used to determine Rcor2 involvement in the modulation of neuroinflammation. The effect of lipopolysaccharide (LPS) treatment on Rcor2 levels and neuroinflammation was analyzed both in vivo and in vitro.

Results

P8 mice presented a dramatic decrease in Rcor2 gene expression compared with R1 controls in splenocytes, an alteration also observed in the brain cortex, hippocampus and primary astrocytes of these mice. Rcor2 reduction in astrocytes was accompanied by an increased basal expression of the interleukin (Il)-6 gene. Strikingly, intraperitoneal LPS injection in R1 mice downregulated Rcor2 in the hippocampus, with a concomitant upregulation of tumor necrosis factor (Tnf-α), Il1-β and Il6 genes. A negative correlation between Rcor2 and Il6 gene expression was also verified in LPS-treated C6 glioma cells. Knock down of Rcor2 by siRNA transfection (siRcor2) in R1 astrocytes upregulated Il6 gene expression while siRcor2 further increased Il6 expression in P8 astrocytes. Moreover, LPS activation provoked a further downregulation of Rcor2 and an amplified induction of Il6 in siRcor2-tranfected astrocytes.

Conclusions

Data presented here show interplay between Rcor2 downregulation and increased inflammation and suggest that Rcor2 may be a key regulator of inflammaging.

【 授权许可】

   
2014 Alvarez-López et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G: Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000, 908:244-254.
• [2]Cevenini E, Monti D, Franceschi C: Inflamm-ageing. Curr Opin Clin Nutr Metab Care 2013, 16:14-20.
• [3]Vasto S, Candore G, Balistreri CR, Caruso M, Colonna-Romano G, Grimaldi MP, Listi F, Nuzzo D, Lio D, Caruso C: Inflammatory networks in ageing, age-related diseases and longevity. Mech Ageing Dev 2007, 128:83-91.
• [4]Kaliman P, Parrizas M: Obesity and systemic inflammation: insight on epigenetic mechanisms. In Role of the Adipocyte in the Development of Type 2 Diabetes, Volume 1st. Edited by Rijeka CC. Croatia: InTech; 2011:65-88.
• [5]Pizza V, Agresta A, D’Acunto CW, Festa M, Capasso A: Neuroinflammation and ageing: current theories and an overview of the data. Rev Recent Clin Trials 2011, 6:189-203.
• [6]Liu Y, Zhang M, Hao W, Mihaljevic I, Liu X, Xie K, Walter S, Fassbender K: Matrix metalloproteinase-12 contributes to neuroinflammation in the aged brain. Neurobiol Aging 2013, 34:1231-1239.
• [7]McGeer PL, McGeer EG: Inflammation and the degenerative diseases of aging. Ann N Y Acad Sci 2004, 1035:104-116.
• [8]Lee M: Neurotransmitters and microglial-mediated neuroinflammation. Curr Protein Pept Sci 2013, 14:21-32.
• [9]Bardou I, Brothers HM, Kaercher RM, Hopp SC, Wenk GL: Differential effects of duration and age on the consequences of neuroinflammation in the hippocampus. Neurobiol Aging 2013, 34:2293-2301.
• [10]Farso M, Menard C, Colby-Milley J, Quirion R: Immune marker CD68 correlates with cognitive impairment in normally aged rats. Neurobiol Aging 2013, 34:1971-1976.
• [11]Lee MG, Wynder C, Cooch N, Shiekhattar R: An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 2005, 437:432-435.
• [12]Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y: Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004, 119:941-953.
• [13]Yang P, Wang Y, Chen J, Li H, Kang L, Zhang Y, Chen S, Zhu B, Gao S: RCOR2 is a subunit of the LSD1 complex that regulates ESC property and substitutes for SOX2 in reprogramming somatic cells to pluripotency. Stem Cells 2011, 29:791-801.
• [14]Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM, Drake D, Liu XS, Bennett DA, Colaiácovo MP, Yankner BA: REST and stress resistance in ageing and Alzheimer’s disease. Nature 2014, 507:448-454.
• [15]Andres ME, Burger C, Peral-Rubio MJ, Battaglioli E, Anderson ME, Grimes J, Dallman J, Ballas N, Mandel G: CoREST: a functional corepressor required for regulation of neural-specific gene expression. Proc Natl Acad Sci U S A 1999, 96:9873-9878.
• [16]Hanzu FA, Musri MM, Sanchez-Herrero A, Claret M, Esteban Y, Kaliman P, Gomis R, Parrizas M: Histone demethylase KDM1A represses inflammatory gene expression in preadipocytes. Obesity (Silver Spring) 2013, 21:E616-E625.
• [17]Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK: A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 2009, 137:47-59.
• [18]Cheng XR, Zhou WX, Zhang YX: The behavioral, pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer’s disease animal model. Ageing Res Rev 2014, 13:13-37.
• [19]Morley JE, Farr SA, Kumar VB, Armbrecht HJ: The SAMP8 mouse: a model to develop therapeutic interventions for Alzheimer’s disease. Curr Pharm Des 2012, 18:1123-1130.
• [20]Pallas M, Camins A, Smith MA, Perry G, Lee HG, Casadesus G: From aging to Alzheimer’s disease: unveiling “the switch” with the senescence-accelerated mouse model (SAMP8). J Alzheimers Dis 2008, 15:615-624.
• [21]Wang H, Lian K, Han B, Wang Y, Kuo SH, Geng Y, Qiang J, Sun M, Wang M: Age-related alterations in the metabolic profile in the hippocampus of the senescence-accelerated mouse prone 8: a spontaneous Alzheimer’s disease mouse model. J Alzheimers Dis 2014, 39:841-848.
• [22]Takeda T, Hosokawa M, Higuchi K: Senescence-accelerated mouse (SAM): a novel murine model of accelerated senescence. J Am Geriatr Soc 1991, 39:911-919.
• [23]Nomura Y, Okuma Y: Age-related defects in lifespan and learning ability in SAMP8 mice. Neurobiol Aging 1999, 20:111-115.
• [24]Morley JE, Armbrecht HJ, Farr SA, Kumar VB: The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer’s disease. Biochim Biophys Acta 2012, 1822:650-656.
• [25]del Valle J, Duran-Vilaregut J, Manich G, Pallas M, Camins A, Vilaplana J, Pelegri C: Cerebral amyloid angiopathy, blood–brain barrier disruption and amyloid accumulation in SAMP8 mice. Neurodegener Dis 2011, 8:421-429.
• [26]Takeda T: Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice. Neurochem Res 2009, 34:639-659.
• [27]Canudas AM, Gutierrez-Cuesta J, Rodriguez MI, Acuna-Castroviejo D, Sureda FX, Camins A, Pallas M: Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM). Mech Ageing Dev 2005, 126:1300-1304.
• [28]Sureda FX, Gutierrez-Cuesta J, Romeu M, Mulero M, Canudas AM, Camins A, Mallol J, Pallas M: Changes in oxidative stress parameters and neurodegeneration markers in the brain of the senescence-accelerated mice SAMP-8. Exp Gerontol 2006, 41:360-367.
• [29]Bayram B, Nikolai S, Huebbe P, Ozcelik B, Grimm S, Grune T, Frank J, Rimbach G: Biomarkers of oxidative stress, antioxidant defence and inflammation are altered in the senescence-accelerated mouse prone 8. Age 2013, 35:1205-1217.
• [30]Garcia-Matas S, Gutierrez-Cuesta J, Coto-Montes A, Rubio-Acero R, Diez-Vives C, Camins A, Pallas M, Sanfeliu C, Cristofol R: Dysfunction of astrocytes in senescence-accelerated mice SAMP8 reduces their neuroprotective capacity. Aging Cell 2008, 7:630-640.
• [31]Cuesta S, Kireev R, Forman K, Garcia C, Escames G, Ariznavarreta C, Vara E, Tresguerres JA: Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8). Exp Gerontol 2010, 45:950-956.
• [32]Cuesta S, Kireev R, Garcia C, Forman K, Escames G, Vara E, Tresguerres JA: Beneficial effect of melatonin treatment on inflammation, apoptosis and oxidative stress on pancreas of a senescence accelerated mice model. Mech Ageing Dev 2011, 132:573-582.
• [33]Cuesta S, Kireev R, Garcia C, Forman K, Vara E, Tresguerres JA: Effect of growth hormone treatment on pancreatic inflammation, oxidative stress, and apoptosis related to aging in SAMP8 mice. Rejuvenation Res 2011, 14:501-512.
• [34]Menardo J, Tang Y, Ladrech S, Lenoir M, Casas F, Michel C, Bourien J, Ruel J, Rebillard G, Maurice T, Puel JL, Wang J: Oxidative stress, inflammation, and autophagic stress as the key mechanisms of premature age-related hearing loss in SAMP8 mouse cochlea. Antioxid Redox Signal 2012, 16:263-274.
• [35]Rodriguez MI, Escames G, Lopez LC, Lopez A, Garcia JA, Ortiz F, Acuna-Castroviejo D: Chronic melatonin treatment reduces the age-dependent inflammatory process in senescence-accelerated mice. J Pineal Res 2007, 42:272-279.
• [36]Wauquier F, Barquissau V, Leotoing L, Davicco MJ, Lebecque P, Mercier S, Philippe C, Miot-Noirault E, Chardigny JM, Morio B, Wittrant Y, Coxam V: Borage and fish oils lifelong supplementation decreases inflammation and improves bone health in a murine model of senile osteoporosis. Bone 2012, 50:553-561.
• [37]Zhao X, Bian Y, Sun Y, Li L, Wang L, Zhao C, Shen Y, Song Q, Qu Y, Niu S, Wu W, Gao F: Effects of moderate exercise over different phases on age-related physiological dysfunction in testes of SAMP8 mice. Exp Gerontol 2013, 48:869-880.
• [38]Tha KK, Okuma Y, Miyazaki H, Murayama T, Uehara T, Hatakeyama R, Hayashi Y, Nomura Y: Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8. Brain Res 2000, 885:25-31.
• [39]Lyman M, Lloyd DG, Ji X, Vizcaychipi MP, Ma D: Neuroinflammation: the role and consequences. Neurosci Res 2014, 79C:1-12.
• [40]Jana M, Palencia CA, Pahan K: Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer’s disease. J Immunol 2008, 181:7254-7262.
• [41]Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, Tylavsky FA, Newman AB: The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004, 292:2237-2242.
• [42]von Bernhardi R: Glial cell dysregulation: a new perspective on Alzheimer disease. Neurotox Res 2007, 12:215-232.