The p38alpha mitogen-activated protein kinase limits the CNS proinflammatory cytokine response to systemic lipopolysaccharide, potentially through an IL-10 dependent mechanism

Journal of Neuroinflammation

Linda J Van Eldik³  Bin Xing²  Adam D Bachstetter¹ 

[1] Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone Street, Lexington 40536, KY, USA;Current Affiliation: VA Pittsburgh Healthcare System, 3501 Fifth Avenue, Pittsburgh 15260, PA, USA;Department of Anatomy and Neurobiology, University of Kentucky, 800 S. Limestone Street, Lexington 40536, KY, USA

关键词: tumor necrosis factor alpha;    signal transduction;    neuroinflammation;    interleukin;    glia;    cytokines;   

Others  :  1150492
DOI  :  10.1186/s12974-014-0175-6

 received in 2014-08-24, accepted in 2014-09-29,  发布年份 2014

【 摘 要 】

Background

The p38? mitogen-activated protein kinase (MAPK) is a well-characterized intracellular kinase involved in the overproduction of proinflammatory cytokines from glia. As such, p38? appears to be a promising therapeutic target for neurodegenerative diseases associated with neuroinflammation. However, the in vivo role of p38? in cytokine production in the CNS is poorly defined, and prior work suggests that p38? may be affecting a yet to be identified negative feedback mechanism that limits the acute, injury-induced proinflammatory cytokine surge in the CNS.

Methods

To attempt to define this negative feedback mechanism, we used two in vitro and two in vivo models of neuroinflammation in a mouse where p38? is deficient in cells of the myeloid lineage.

Results

We found that p38? in myeloid cells has an important role in limiting amplitude of the acute proinflammatory cytokine response to a systemic inflammatory challenge. Moreover, we identified IL-10 as a potential negative feedback mechanism regulated by p38?.

Conclusions

Our data suggest that p38? regulates a proper balance between the pro- and anti-inflammatory cytokine responses to systemic inflammation, and that if circulating IL-10 levels are not elevated to counter-balance the increased systemic proinflammatory responses, the spread of the inflammatory response from the periphery to the CNS is exaggerated.

【 授权许可】

   
2014 Bachstetter et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Mrak RE, Griffin WST: Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 2005, 26:349-354.
• [2]Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH: Mechanisms underlying inflammation in neurodegeneration. Cell 2010, 140:918-934.
• [3]Wyss-Coray T, Rogers J: Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2012, 2:a006346.
• [4]Tansey MG, Goldberg MS: Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 2010, 37:510-518.
• [5]Das M, Mohapatra S, Mohapatra SS: New perspectives on central and peripheral immune responses to acute traumatic brain injury. J Neuroinflammation 2012, 9:236. BioMed Central Full Text
• [6]David S, Kroner A: Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011, 12:388-399.
• [7]Iadecola C, Anrather J: The immunology of stroke: from mechanisms to translation. Nat Med 2011, 17:796-808.
• [8]Van Eldik LJ, Thompson WL, Ralay Ranaivo H, Behanna HA, Martin Watterson D: Glia proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative diseases: function-based and target-based discovery approaches. Int Rev Neurobiol 2007, 82:277-296.
• [9]McCoy MK, Tansey MG: TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 2008, 5:45. BioMed Central Full Text
• [10]Li Y, Liu L, Barger SW, Griffin WS: Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 2003, 23:1605-1611.
• [11]Sheng JG, Jones RA, Zhou XQ, McGinness JM, Van Eldik LJ, Mrak RE, Griffin WS: Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation. Neurochem Int 2001, 39:341-348.
• [12]Bachstetter AD, Van Eldik LJ: The p38 MAP kinase family as regulators of proinflammatory cytokine production in degenerative diseases of the CNS. Aging Dis 2010, 1:199-211.
• [13]Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, Strickler JE, Mclaughlin MM, Siemens IR, Fisher SM, Livi GP, White JR, Adams JL, Young PR: A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 1994, 372:739-746.
• [14]Margutti S, Laufer SA: Are MAP kinases drug targets? Yes, but difficult ones. Chem Med Chem 2007, 2:1116-1140.
• [15]Hammaker D, Firestein GS: "Go upstream, young man": lessons learned from the p38 saga. Ann Rheum Dis 2010, 69(Suppl 1):i77-i82.
• [16]Munoz L, Ranaivo HR, Roy SM, Hu W, Craft JM, McNamara LK, Chico LW, Van Eldik LJ, Watterson DM: Novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model. J Neuroinflammation 2007, 4:21. BioMed Central Full Text
• [17]Watterson DM, Grum-Tokars VL, Roy SM, Schavocky JP, Bradaric BD, Bachstetter AD, Xing B, Dimayuga E, Saeed F, Zhang H, Staniszewski A, Pelletier JC, Minasov G, Anderson WF, Arancio O, Van Eldik LJ: Development of novel chemical probes to address CNS protein kinase involvement in synaptic dysfunction. PLoS One 2013, 8:e66226.
• [18]Sugino T, Nozaki K, Takagi Y, Hattori I, Hashimoto N, Moriguchi T, Nishida E: Activation of mitogen-activated protein kinases after transient forebrain ischemia in gerbil hippocampus. J Neurosci 2000, 20:4506-4514.
• [19]Piao CS, Kim JB, Han PL, Lee JK: Administration of the p38 MAPK inhibitor SB203580 affords brain protection with a wide therapeutic window against focal ischemic insult. J Neurosci Res 2003, 73:537-544.
• [20]Legos JJ, Erhardt JA, White RF, Lenhard SC, Chandra S, Parsons AA, Tuma RF, Barone FC: SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia. Brain Res 2001, 892:70-77.
• [21]Barone FC, Irving EA, Ray AM, Lee JC, Kassis S, Kumar S, Badger AM, White RF, McVey MJ, Legos JJ, Erhardt JA, Nelson AH, Ohlstein EH, Hunter AJ, Ward K, Smith BR, Adams JL, Parsons AA: SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia. J Pharmacol Exp Ther 2001, 296:312-321.
• [22]Jin SX, Zhuang ZY, Woolf CJ, Ji RR: p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci 2003, 23:4017-4022.
• [23]Kim SW, Yu YM, Piao CS, Kim JB, Lee JK: Inhibition of delayed induction of p38 mitogen-activated protein kinase attenuates kainic acid-induced neuronal loss in the hippocampus. Brain Res 2004, 1007:188-191.
• [24]Fisk M, Gajendragadkar PR, Maki-Petaja KM, Wilkinson IB, Cheriyan J: Therapeutic potential of p38 MAP kinase inhibition in the management of cardiovascular disease. Am J Cardiovasc Drugs 2014, 14:155-165.
• [25]Huang G, Wang Y, Vogel P, Kanneganti TD, Otsu K, Chi H: Signaling via the kinase p38alpha programs dendritic cells to drive TH17 differentiation and autoimmune inflammation. Nat Immunol 2012, 13:152-161.
• [26]Munoz L, Ammit AJ: Targeting p38 MAPK pathway for the treatment of Alzheimer's disease. Neuropharmacology 2010, 58:561-568.
• [27]Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ: Microglial p38alpha MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Abeta). J Neuroinflammation 2011, 8:79. BioMed Central Full Text
• [28]Bachstetter AD, Rowe RK, Kaneko M, Goulding D, Lifshitz J, Van Eldik LJ: The p38alpha MAPK regulates microglial responsiveness to diffuse traumatic brain injury. J Neurosci 2013, 33:6143-6153.
• [29]Kang YJ, Chen J, Otsuka M, Mols J, Ren S, Wang Y, Han J: Macrophage deletion of p38alpha partially impairs lipopolysaccharide-induced cellular activation. J Immunol 2008, 180:5075-5082.
• [30]Clausen BE, Burkhardt C, Reith W, Renkawitz R, Forster I: Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res 1999, 8:265-277.
• [31]Clarke S, Greaves DR, Chung LP, Tree P, Gordon S: The human lysozyme promoter directs reporter gene expression to activated myelomonocytic cells in transgenic mice. Proc Natl Acad Sci U S A 1996, 93:1434-1438.
• [32]Xing B, Bachstetter AD, Eldik LJ: Microglial p38alpha MAPK is critical for LPS-induced neuron degeneration, through a mechanism involving TNFalpha. Mol Neurodegener 2011, 6:84. BioMed Central Full Text
• [33]Petrova TV, Akama KT, Van Eldik LJ: Cyclopentenone prostaglandins suppress activation of microglia: Down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta(12,14)-prostaglandin J(2). Proc Natl Acad Sci U S A 1999, 96:4668-4673.
• [34]Davies JQ, Gordon S: Isolation and culture of murine macrophages. Methods Mol Biol 2005, 290:91-103.
• [35]Zhang X, Goncalves R, Mosser DM: The isolation and characterization of murine macrophages.Curr Protoc Immunol 2008, Chapter 14:Unit 14.1. doi:10.1002/0471142735.im1401s83.
• [36]Pino PA, Cardona AE: Isolation of brain and spinal cord mononuclear cells using percoll gradients. J Vis Exp 2011, 48:2348.
• [37]Bachstetter AD, Norris CM, Sompol P, Wilcock DM, Goulding D, Neltner JH, St Clair D, Watterson DM, Van Eldik LJ: Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer's disease-related pathology. J Neurosci 2012, 32:10201-10210.
• [38]Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL: Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 2014, 17:131-143.
• [39]Goldmann T, Wieghofer P, Müller PF, Wolf Y, Varol D, Yona S, Brendecke SM, Kierdorf K, Staszewski O, Datta M, Luedde T, Heikenwalder M, Jung S, Prinz M: A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci 2013, 16:1618-1626.
• [40]Mizutani M, Pino PA, Saederup N, Charo IF, Ransohoff RM, Cardona AE: The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol 2012, 188:29-36.
• [41]Darragh J, Ananieva O, Courtney A, Elcombe S, Arthur JS: MSK1 regulates the transcription of IL-1ra in response to TLR activation in macrophages. Biochem J 2010, 425:595-602.
• [42]Ananieva O, Darragh J, Johansen C, Carr JM, McIlrath J, Park JM, Wingate A, Monk CE, Toth R, Santos SG, Iversen L, Arthur JS: The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nat Immunol 2008, 9:1028-1036.
• [43]Kim C, Sano Y, Todorova K, Carlson BA, Arpa L, Celada A, Lawrence T, Otsu K, Brissette JL, Arthur JS, Park JM: The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat Immunol 2008, 9:1019-1027.
• [44]Bachstetter AD, Watterson DM, Van Eldik LJ: Target engagement analysis and link to pharmacodynamic endpoint for a novel class of CNS-penetrant and efficacious p38alpha MAPK inhibitors. J Neuroimmune Pharmacol 2014, 9:454-460.
• [45]Xing B, Bachstetter AD, Van Eldik LJ: Deficiency in p38beta MAPK fails to inhibit cytokine production or protect neurons against inflammatory insult in in vitro and in vivo mouse models. PLoS One 2013, 8:e56852.
• [46]Xing B, Bachstetter AD, Van Eldik LJ: Inhibition of neuronal p38alpha, but not p38beta MAPK, provides neuroprotection against three different neurotoxic insults.J Mol Neurosci 2014, [Epub ahead of print].
• [47]Chakravarty S, Herkenham M: Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J Neurosci 2005, 25:1788-1796.
• [48]Engström L, Ruud J, Eskilsson A, Larsson A, Mackerlova L, Kugelberg U, Qian H, Vasilache AM, Larsson P, Engblom D, Sigvardsson M, Jönsson JI, Blomqvist A: Lipopolysaccharide-induced fever depends on prostaglandin E2 production specifically in brain endothelial cells. Endocrinology 2012, 153:4849-4861.
• [49]Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R, Yin X, Kidd GJ, Bergmann CC, Stohlman SA, Trapp BD: Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J Neurosci 2012, 32:11706-11715.
• [50]Quan N: Immune-to-brain signaling: How important are the blood¿brain barrier-independent pathways? Mol Neurobiol 2008, 37:142-152.
• [51]Laflamme N, Lacroix S, Rivest S: An essential role of interleukin-1 beta in mediating NF-kappa B activity and COX-2 transcription in cells of the blood¿brain barrier in response to a systemic and localized inflammation but not during endotoxemia. J Neurosci 1999, 19:10923-10930.
• [52]Saraiva M, O'Garra A: The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010, 10:170-181.
• [53]Bluthe RM, Castanon N, Pousset F, Bristow A, Ball C, Lestage J, Michaud B, Kelley KW, Dantzer R: Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats. Psychoneuroendocrinology 1999, 24:301-311.
• [54]Di Santo E, Adami M, Bertorelli R, Ghezzi P: Systemic interleukin 10 administration inhibits brain tumor necrosis factor production in mice. Eur J Pharmacol 1997, 336:197-202.
• [55]Bethea JR, Nagashima H, Acosta MC, Briceno C, Gomez F, Marcillo AE, Loor K, Green J, Dietrich WD: Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats. J Neurotrauma 1999, 16:851-863.
• [56]Krzyszton CP, Sparkman NL, Grant RW, Buchanan JB, Broussard SR, Woods J, Johnson RW: Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation. Am J Physiol Regu Integr Comp Physiol 2008, 295:R1109-R1114.
• [57]Norden DM, Fenn AM, Dugan A, Godbout JP: TGFbeta produced by IL-10 redirected astrocytes attenuates microglial activation. Glia 2014, 62:881-895.
• [58]Pils MC, Pisano F, Fasnacht N, Heinrich JM, Groebe L, Schippers A, Rozell B, Jack RS, Muller W: Monocytes/macrophages and/or neutrophils are the target of IL-10 in the LPS endotoxemia model. Eur J Immunol 2010, 40:443-448.
• [59]Guma M, Hammaker D, Topolewski K, Corr M, Boyle DL, Karin M, Firestein GS: Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKK-6. Arthritis Rheum 2012, 64:2887-2895.
• [60]Arthur JS: MSK activation and physiological roles. Front Biosci 2008, 13:5866-5879.
• [61]Ehlting C, Ronkina N, Böhmer O, Albrecht U, Bode KA, Lang KS, Kotlyarov A, Radzioch D, Gaestel M, Häussinger D, Bode JG: Distinct functions of the mitogen-activated protein kinase-activated protein (MAPKAP) kinases MK2 and MK3: MK2 mediates lipopolysaccharide-induced signal transducers and activators of transcription 3 (STAT3) activation by preventing negative regulatory effects of MK3. J Biol Chem 2011, 286:24113-24124.