MAPK-activated Protein Kinase 2 Deficiency in Microglia Inhibits Pro-inflammatory Mediator Release and Resultant Neurotoxicity

Abstract

MAPK-activated protein kinase 2 (MAPKAP K2 or MK2) is one of several kinases directly regulated by p38 MAPK. A role for p38 MAPK in the pathology of Alzheimer disease (AD) has previously been suggested. Here, we provide evidence to suggest that MK2 also plays a role in neuroinflammatory and neurodegenerative pathology of relevance to AD. MK2 activation and expression were increased in lipopolysaccharide (LPS) + interferon γ-stimulated microglial cells, implicating a role for MK2 in eliciting a pro-inflammatory response. Microglia cultured ex vivo from MK2-deficient (MK2–/–) mice demonstrated significant inhibition in release of tumor necrosis factor α, KC (mouse chemokine with highest sequence identity to human GROs and interleukin-8), and macrophage inflammatory protein 1α on stimulation with LPS + interferon γ or amyloid-β peptide (1–42) compared with MK2+/+ wild-type microglia. Consistent with an inhibition in pro-inflammatory mediator release, cortical neurons co-cultured with LPS + interferon γ-stimulated or amyloid-β peptide (1–42)-stimulated MK2–/– microglia were protected from microglial-mediated neuronal cell toxicity. In a transgenic mouse model of AD in which amyloid precursor protein and presenilin-1 harboring familial AD mutations are overexpressed in specific regions of the brain, elevated activation and expression of MK2 correlated with β-amyloid deposition, microglial activation, and up-regulation of tumor necrosis factor α, macrophage inflammatory protein 1α, and KC gene expression in the same brain regions. Our data propose a role for MK2 in AD brain pathology, for which neuroinflammation involving cytokines and chemokines and overt neuronal loss have been documented. MAPK-activated protein kinase 2 (MAPKAP K2 or MK2) is one of several kinases directly regulated by p38 MAPK. A role for p38 MAPK in the pathology of Alzheimer disease (AD) has previously been suggested. Here, we provide evidence to suggest that MK2 also plays a role in neuroinflammatory and neurodegenerative pathology of relevance to AD. MK2 activation and expression were increased in lipopolysaccharide (LPS) + interferon γ-stimulated microglial cells, implicating a role for MK2 in eliciting a pro-inflammatory response. Microglia cultured ex vivo from MK2-deficient (MK2–/–) mice demonstrated significant inhibition in release of tumor necrosis factor α, KC (mouse chemokine with highest sequence identity to human GROs and interleukin-8), and macrophage inflammatory protein 1α on stimulation with LPS + interferon γ or amyloid-β peptide (1–42) compared with MK2+/+ wild-type microglia. Consistent with an inhibition in pro-inflammatory mediator release, cortical neurons co-cultured with LPS + interferon γ-stimulated or amyloid-β peptide (1–42)-stimulated MK2–/– microglia were protected from microglial-mediated neuronal cell toxicity. In a transgenic mouse model of AD in which amyloid precursor protein and presenilin-1 harboring familial AD mutations are overexpressed in specific regions of the brain, elevated activation and expression of MK2 correlated with β-amyloid deposition, microglial activation, and up-regulation of tumor necrosis factor α, macrophage inflammatory protein 1α, and KC gene expression in the same brain regions. Our data propose a role for MK2 in AD brain pathology, for which neuroinflammation involving cytokines and chemokines and overt neuronal loss have been documented. The role of p38 mitogen-activated protein kinase (MAPK) 2The abbreviations used are: MAPK, mitogen-activated protein kinase; MK2, MAPK-activated protein kinase 2; AD, Alzheimer disease; CNS, central nervous system; LPS, lipopolysaccharide; IFNγ, interferon γ; TNF-α, tumor necrosis factor-α; MIP-1α, macrophage inflammatory protein 1α; WT, wild type; Aβ, β-amyloid protein; FCS, fetal calf serum; LDH, lactate dehydrogenase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; RT, reverse transcriptase; IL, interleukin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. 2The abbreviations used are: MAPK, mitogen-activated protein kinase; MK2, MAPK-activated protein kinase 2; AD, Alzheimer disease; CNS, central nervous system; LPS, lipopolysaccharide; IFNγ, interferon γ; TNF-α, tumor necrosis factor-α; MIP-1α, macrophage inflammatory protein 1α; WT, wild type; Aβ, β-amyloid protein; FCS, fetal calf serum; LDH, lactate dehydrogenase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; RT, reverse transcriptase; IL, interleukin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. in the regulation of cytokine biosynthesis is now well estab lished (1Han J. Lee J.D. Bibbs L. Ulevitch R.J. Science. 1994; 265: 808-811Crossref PubMed Scopus (2390) Google Scholar, 2Lee J.C. Laydon J.T. McDonnell P.C. Gallagher T.F. Kumar S. Green D. McNulty D. Blumenthal M.J. Heys J.R. Landvatter S.W. Strickler J.E. McLaughlin M.M. Siemens I.R. Fisher S.M. Livi G.P. White J.R. Adams J.L. Young P.R. Nature. 1994; 372: 739-746Crossref PubMed Scopus (3113) Google Scholar). MAPK-activated protein kinase 2 (MK2) is one of several kinases that are regulated through direct phosphorylation by p38 MAPK, and MK2 has therefore been a candidate for an effector role in p38 action in the inflammatory response. Studies using MK2–/– mice support this hypothesis, because mice lacking MK2 are resistant to endotoxic shock, largely due to a reduction in serum tumor necrosis factor-α (TNF-α) levels (3Kotlyarov A. Neininger A. Schubert C. Eckert R. Birchmeier C. Volk H.D. Gaestel M. Nat. Cell Biol. 1999; 1: 94-97Crossref PubMed Scopus (675) Google Scholar). Furthermore, macrophages and spleen cells taken from MK2-deficient animals show inhibition in the release of a range of pro-inflammatory mediators (3Kotlyarov A. Neininger A. Schubert C. Eckert R. Birchmeier C. Volk H.D. Gaestel M. Nat. Cell Biol. 1999; 1: 94-97Crossref PubMed Scopus (675) Google Scholar, 4Kotlyarov A. Gaestel M. Biochem. Soc. Trans. 2002; 30: 959-963Crossref PubMed Scopus (76) Google Scholar). Alzheimer disease (AD) is a neurodegenerative disorder that affects primarily hippocampal and neocortical brain regions resulting in a progressive loss of cognitive and memory function and ultimately dementia. Post-mortem diagnosis of AD is facilitated by the presence of extracellular plaques comprising β-amyloid protein (Aβ), and neuroinflammation is a persistent pathological hallmark. Microglia, the resident macrophages of the brain, are responsible for eliciting such an immune response in the CNS. These immune cells of monocytic lineage are activated by a wide range of stimuli and release pro-inflammatory mediators that, in turn, induce microglial autoactivation, thereby amplifying the inflammatory response. It has been proposed that elevated levels of β-amyloid in AD brain induces microglial activation and consequent release of pro-inflammatory cytokines, chemokines, and other potentially neurotoxic substances (5McGeer P.L. McGeer E.G. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2003; 5: 741-749Crossref Scopus (460) Google Scholar, 6McGeer P.L. McGeer E.G. Neurobiol. Aging. 2001; 22: 799-809Crossref PubMed Scopus (435) Google Scholar, 7Akiyama H. Barger S. Barnum S. Bradt B. Bauer J. Cole G.M. Cooper N.R. Eikelenboom P. Emmerling M. Fiebich B. Finch C.E. Frautschy S. Griffin W.S.T. Hampel H. Hull M. Landreth G. Lue L.F. Mrak R. Mackenzie I.R. McGeer P.L. O'Banion M.K. Pachter J. Pasinetti G. Plata-Salaman C. Rogers J. Rydel R. Shen Y. Streit W. Strohmeyer R. Tooyama I. 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Chem. 2003; 278: 13309-13317Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar). The neuroinflammatory changes and microglial activation observed in AD pathology are therefore hypothesized to contribute to neuronal cell loss and associated dementia in this disease, well neuronal and in other resulting from or L.T. Neurochem. PubMed Scopus Google Scholar, D. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Nature. 2001; Scopus Google Scholar). of the inflammatory response the of AD through a reduction in by activation of microglia P.L. M. McGeer E.G. PubMed Scopus Google Scholar, C. M. PubMed Scopus Google Scholar, J.C. L. 2002; PubMed Scopus Google Scholar). of of to AD pathology is therefore of of the p38 MAPK has been to inflammatory pathology in AD and in mouse of the disease R. J. G. J. Neurochem. 1999; PubMed Scopus Google Scholar, C. C. A. S. G. Neurobiol. 2002; PubMed Scopus Google Scholar, M. G. R. A. M. J. D. J. S. A. 2002; PubMed Scopus Google Scholar, Lee PubMed Scopus Google Scholar). In p38 MAPK in cultured microglial cells C. B. R. P. A. J. 2001; PubMed Scopus Google Scholar). MK2 is an kinase of p38 MAPK, we hypothesized that MK2 a role in neuroinflammation and to AD. we have the role of MK2 in microglial cell activation, and the on microglial-mediated neuronal cell toxicity. In we have correlated in vitro with a role for MK2 in a transgenic mouse model of AD. and fetal calf serum and mouse and were from lipopolysaccharide and were from from from for reverse were from and mouse and were from from for were to (mouse and and for for by were to and from for to p38 MAPK, MAPK and MK2 were from Cell The MK2 kinase from Cell and the from and cytokine enzyme-linked immunosorbent were from peptide from Cell and were from which are transgenic mice the of human amyloid precursor protein harboring the familial Alzheimer disease and human presenilin-1 harboring the familial were and in previously J.C. C.E. R. P. R. S. D. J.C. R. 2003; PubMed Scopus Google Scholar, J.C. A. Bate PubMed Scopus Google Scholar). In this transgenic are the of the which expression to the and the of in progressive amyloid and pathology in the ex vivo animals were by of a of MK2–/– mice were in the of Gaestel and to on a previously (3Kotlyarov A. Neininger A. Schubert C. Eckert R. Birchmeier C. Volk H.D. Gaestel M. Nat. Cell Biol. 1999; 1: 94-97Crossref PubMed Scopus (675) Google Scholar). Microglia were cultured ex vivo from wild-type and MK2–/– mice of microglial cells were cultured previously J. PubMed Scopus Google Scholar). were to 2 to cell stimulation with LPS and IFNγ, or In from microglial cells or cortical from and mice were for MK2 using the MK2 kinase Cell to the In were from microglial cells by cell in PBS, by in the mouse cortical and protein were previously Biol. 2001; Google Scholar). were by and MK2 from of were by MK2 for with of in the kinase of used a of MK2 and MK2 by by were using and by from from and cells, and microglial cells using to the from of and of the resulting for were in previously R. L. 2001; PubMed Scopus Google Scholar). were using to a to and and were from mouse or in the data using mouse and mouse and mouse and mouse MK2 and MK2 and mouse KC and the and the the for and from mice were in the and in in phosphate-buffered for The brain and were and to the were through a of and in by for and Aβ, were by in by in for were in in for to of plaques and were with the and the mouse to in and serum in with in in by and using and to the data of microglia were from of of C. J. Neurochem. PubMed Scopus Google Scholar). were in with the The cell from in with with and + and in a of and Microglia were on by the on an for 2 The cell were in The to and for to of microglia. The microglial cells were in for to neuronal cell cell from and MK2–/– mice were also microglia were from cell for that animals were used cell mouse microglia were used for cytokine release and in of cortical neurons and mouse microglia. mouse microglia were in the same microglia from from Microglia and were in of a a of cells well and to were to release pro-inflammatory mediators in LPS and mouse IFNγ, or to cell peptide for this by the peptide in to a of The and the peptide in to a of to and to the peptide to to cells to a of Cell were and cytokine and chemokine release by to the LPS + or cell by or to the of cortical cell were from of L. D. A. G. in with of were and with a the were in 2 and and in in were to to cell 2 of were in a cells were used on for of Microglia and were by for cells were in 2 and were by a of microglia or on neurons for in vitro in a were for and with to and and with in LPS + were the of microglia to the neuronal cell with an of LPS and or mouse were for of cortical neurons or microglia. were for which cell by in LPS + release the used a of cell and has been previously to neuronal cell in S. Chandran S. Brown G.C. Compston A. J. Neurochem. 2002; 82: 269-282Crossref PubMed Scopus (74) Google Scholar, 13Parvathenani L.K. Tertyshnikova S. Greco C.R. Roberts S.B. Robertson B. Posmantur R. J. Biol. 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G. in Scholar). are or to were by or by of by for involving data MK2 in with and the expression of MK2 in cell the CNS, we compared expression of MK2 in of cortical and by and expression of and MK2 expression to in microglial cells, a role for MK2 function in MK2 p38 MAPK and MK2 in with LPS + expression of MK2 in microglial cells and response to a pro-inflammatory microglial cells were with LPS + and MK2 expression by of microglia such of MK2 expression observed and of LPS + in MK2 gene expression by an in phosphorylation of p38 MAPK and an in MK2 by phosphorylation of in vitro by MK2 from LPS + of p38 MAPK phosphorylation and MK2 observed MK2 expression also with LPS + MK2 in Microglia LPS + and and of microglial cells and cortical microglia with LPS + an of pro-inflammatory mediators by of microglial with peptide in the release of reverse peptide from the same the peptide to a role for MK2 in mediator release from ex vivo of microglia from of MK2–/– and wild-type mice were and the cells were with LPS + or MK2–/– microglia demonstrated significant in MIP-1α, TNF-α, and KC release on with LPS + IFNγ, and a significant reduction in release on with peptide Cell wild-type and MK2–/– mediators from mouse microglia and mouse microglial + in a LPS + Microglia in with co-cultured cortical neurons in and microglia to microglia with LPS + directly cause neuronal cell The of LPS + on well neuronal and microglial by release the this release increased with in the significant neuronal cell death a of for of with or LPS with microglia in release that to loss of neurons and that neuronal cell death microglial stimulation LPS + cortical were also for the and using cultured in the presence of LPS + microglia for a of by and loss of cell These data are in in and are with an in release that neuronal cell LPS + direct on release from neuronal cell and for or from activated or microglia on neuronal cell in vitro for neurotoxic for LPS + microglia have been by S. 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Neurochem. 2002; 82: 269-282Crossref PubMed Scopus (74) Google Scholar). from LPS + microglia to induce neuronal cell we have that activated microglia and neurons is for demonstrated by microglia on a and were to with an of cortical The microglia were by LPS + IFNγ, and neuronal cell by for in cortical that microglia were by with LPS and data that from LPS + microglia are in for neuronal cell and that MK2 the of LPS + Microglia on the of MK2 in neuronal cell by LPS + cortical neurons were co-cultured with microglia from MK2-deficient and wild-type with wild-type microglia and with LPS + significant neuronal cell death to the of LPS + microglia co-cultured with cortical In of cortical neurons and microglia from MK2-deficient with LPS + were of p38 MAPK in LPS + MK2–/– microglia with that of wild-type LPS + stimulation of this kinase of MK2 in MK2–/– microglia MK2 the of Microglia on microglial cells activated by are neurotoxic and MK2 plays a The model by microglia from wild-type and MK2–/– mice on cell a by to with an of cortical The microglia were with and neuronal cell by this of to the neuronal cell in the of microglia. microglia a loss of neuronal cell which MK2–/– microglia were used MK2 in with in MIP-1α, TNF-α, and KC and observed up-regulation of MK2 expression in activated microglial cells in vitro an of MK2 gene and microglial activation in the transgenic mouse model of AD. mice are a transgenic that of human amyloid precursor protein and presenilin-1 in the CNS, resulting in progressive amyloid and pathology in the brain J.C. 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In MK2–/– to microglial cell of protein and in the presence of LPS + The of in release from LPS + microglia is in to of MK2 regulation of expression of this cytokine in other the that MK2 to the regulation of expression in LPS + microglia that of TNF-α, and Our are the to a role of MK2 in release in LPS + MK2–/– also in cells with It to the of MK2 on other pro-inflammatory the pro-inflammatory mediator by from microglial Indeed, we and have that stimulation of microglial with peptide can induce expression of cytokines and chemokines the the pro-inflammatory mediator the protein in cell These data suggest that expression is to and that MK2 plays a role in of The that MK2 plays a role in TNF-α, and release from LPS + and microglia correlated well with up-regulation of expression of same cytokines in cortical of in which up-regulation of MK2 expression and has also been In a of in levels were in from mice compared with These data propose a role for MK2 in neuroinflammation resulting from β-amyloid pathology in AD brain A direct MK2-deficient mice with which is the of the Indeed, up-regulation of chemokine and cytokine expression has been in AD brain (5McGeer P.L. 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