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Telmisartan Protects a Microglia Cell Line from LPS Injury Beyond AT1 Receptor Blockade or PPARγ Activation

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Abstract

The Angiotensin II Receptor Blocker (ARB) Telmisartan reduces inflammation through Angiotensin II AT1 receptor blockade and peroxisome proliferator-activated receptor gamma (PPARγ) activation. However, in a mouse microglia-like BV2 cell line, imitating primary microglia responses with high fidelity and devoid of AT1 receptor gene expression or PPARγ activation, Telmisartan reduced gene expression of pro-injury factors, enhanced that of anti-inflammatory genes, and prevented LPS-induced increase in inflammatory markers. Using global gene expression profiling and pathways analysis, we revealed that Telmisartan normalized the expression of hundreds of genes upregulated by LPS and linked with inflammation, apoptosis and neurodegenerative disorders, while downregulating the expression of genes associated with oncological, neurodegenerative and viral diseases. The PPARγ full agonist Pioglitazone had no neuroprotective effects. Surprisingly, the PPARγ antagonists GW9662 and T0070907 were neuroprotective and enhanced Telmisartan effects. GW9226 alone significantly reduced LPS toxic effects and enhanced Telmisartan neuroprotection, including downregulation of pro-inflammatory TLR2 gene expression. Telmisartan and GW9662 effects on LPS injury negatively correlated with pro-inflammatory factors and upstream regulators, including TLR2, and positively with known neuroprotective factors and upstream regulators. Gene Set Enrichment Analysis (GSEA) of the Telmisartan and GW9662 data revealed negative correlations with sets of genes associated with neurodegenerative and metabolic disorders and toxic treatments in cultured systems, while demonstrating positive correlations with gene sets associated with neuroprotection and kinase inhibition. Our results strongly suggest that novel neuroprotective effects of Telmisartan and GW9662, beyond AT1 receptor blockade or PPARγ activation, include downregulation of the TLR2 signaling pathway, findings that may have translational relevance.

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References

  1. Mamik MK, Power C (2017) Inflammasomes in neurological diseases: emerging pathogenic and therapeutic concepts. Brain 140:2273–2285. https://doi.org/10.1093/brain/awx133

    Article  PubMed  Google Scholar 

  2. Villapol S (2018) Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell Mol Neurobiol 38:121–132. https://doi.org/10.1007/s10571-017-0554-5

    Article  CAS  PubMed  Google Scholar 

  3. Kabba JA, Xu Y, Christian H, Ruan W, Chenai K, Xiang Y, Zhang L, Saavedra JM et al (2018) Microglia: housekeeper of the central nervous system. Cell Mol Neurobiol 38:53–71. https://doi.org/10.1007/s10571-017-0504-2

    Article  CAS  PubMed  Google Scholar 

  4. von Bernhardi R, Eugenín-von Bernhardi L, Eugenín J (2015) Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci 7:124. https://doi.org/10.3389/fnagi.2015.00124

    Article  CAS  Google Scholar 

  5. Salter MW, Stevens B (2017) Microglia emerge as central players in brain disease. Nat Med 23:1018–1027. https://doi.org/10.1038/nm.4397

    Article  CAS  PubMed  Google Scholar 

  6. Saavedra JM, Sánchez-Lemus E, Benicky J (2011) Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications. Psychoneuroendocrinology 36:1–18. https://doi.org/10.1016/j.psyneuen.2010.10.001

    Article  CAS  PubMed  Google Scholar 

  7. Jarrott B, Williams SJ (2016) Chronic brain inflammation: the neurochemical basis for drugs to reduce inflammation. Neurochem Res 41:523–533. https://doi.org/10.1007/s11064-015-1661-7

    Article  CAS  PubMed  Google Scholar 

  8. Saavedra JM (2017) Beneficial effects of angiotensin II receptor blockers in brain disorders. Pharmacol Res 125(Pt A):91–103. https://doi.org/10.1016/j.phrs.2017.06.017

    Article  CAS  PubMed  Google Scholar 

  9. Saavedra JM (2012) Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond) 123:567–590. https://doi.org/10.1042/CS20120078

    Article  CAS  Google Scholar 

  10. 10.Villapol S, Yaszemski AK, Logan TT, Sánchez-Lemus E, Saavedra JM, Symes AJ. (2012) Candesartan, an angiotensin II AT1-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice. Neuropsychopharmacology 37:2817–2829. https://doi.org/10.1038/npp.2012.152.

    Article  CAS  Google Scholar 

  11. Danielyan L, Lourhmati A, Verleysdonk S, Kabisch D, Proksch B, Thiess U, Umbreen S, Schmidt B et al (2007) Angiotensin receptor type 1 blockade in astroglia decreases hypoxia-induced cell damage and TNF alpha release. Neurochem Res 32:1489–1498. https://doi.org/10.1007/s11064-007-9337-6

    Article  CAS  PubMed  Google Scholar 

  12. Danielyan L, Klein R, Hanson LR, Buadze M, Schwab M, Gleiter CH, Frey WH (2010) Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuvenation Res 13:195–201. https://doi.org/10.1089/rej.2009.0944

    Article  CAS  PubMed  Google Scholar 

  13. Benicky J, Sánchez-Lemus E, Honda M, Pang T, Orecna M, Wang J, Leng Y, Chuang DM et al (2011) Angiotensin II AT1 receptor blockade ameliorates brain inflammation. Neuropsychopharmacology 36:857–870. https://doi.org/10.1038/npp.2010.225

    Article  CAS  PubMed  Google Scholar 

  14. Wang J, Pang T, Hafko R, Benicky J, Sanchez-Lemus E, Saavedra JM (2014a) Telmisartan ameliorates glutamate-induced neurotoxicity: roles of AT(1) receptor blockade and PPARγ activation. Neuropharmacology 79:249–261. https://doi.org/10.1016/j.neuropharm.2013.11.022

    Article  CAS  PubMed  Google Scholar 

  15. Villapol S, Balarezo MG, Affram K, Saavedra JM, Symes AJ (2015) Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Brain 138(Pt 11):3299–3315. https://doi.org/10.1093/brain/awv172

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lund S, Christensen KV, Hedtjärn M, Mortensen AL, Hagberg H, Falsig J, Hasseldam H, Schrattenholz A et al (2006) The dynamics of the LPS triggered inflammatory response of murine microglia under different culture and in vivo conditions. J Neuroimmunol 180:71–87. https://doi.org/10.1016/j.jneuroim.2006.07.007

    Article  CAS  PubMed  Google Scholar 

  17. Xu Y, Xu Y, Wang Y, Wang Y, He L, Jiang Z, Huang Z, Liao H et al (2015) Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKKβ-dependent AMPK activation. Brain Behav Immun 50:298–313. https://doi.org/10.1016/j.bbi.2015.07.015

    Article  CAS  PubMed  Google Scholar 

  18. Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, Qi N, Wang J et al (2004) Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 43:993–1002

    Article  CAS  Google Scholar 

  19. Destro M, Cagnoni F, Dognini GP, Galimberti V, Taietti C, Cavalleri C, Galli E (2011) Telmisartan: just an antihypertensive agent? A literature review. Expert Opin Pharmacother 12:2719–2735. https://doi.org/10.1517/14656566.2011.632367

    Article  CAS  PubMed  Google Scholar 

  20. Gillies PS, Dunn CJ (2000) Pioglitazone. Drugs 60:333–343

    Article  CAS  Google Scholar 

  21. Zaytseva YY, Wallis NK, Southard RC, Kilgore MW (2011) The PPARgamma antagonist T0070907 suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms. Anticancer Res 31:813–823

    CAS  PubMed  Google Scholar 

  22. Chen HY, Xu Z, Chen LF, Wang W, Fang Q, Yan XW (2012) Valsartan and telmisartan abrogate angiotensin II-induced downregulation of ABCA1 expression via AT1 receptor, rather than AT2 receptor or PPARγ activation. J Cardiovasc Pharmacol 59:570–575. https://doi.org/10.1097/FJC.0b013e31824fc5e3

    Article  CAS  PubMed  Google Scholar 

  23. Horvath R, McMenemy N, Alkaitis M, DeLeo J (2008) Differential migration, LPS-induced cytokine, chemokine, and NO expression in immortalized BV-2 and HAPI cell lines and primary microglia cultures. J Neurochem 107:557–569. https://doi.org/10.1111/j.1471-4159.2008.05633.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Henn A, Lund S, Hedtjärn M, Schrattenholz A, Pörzgen P, Leist M (2009) The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. ALTEX 26:83–94. https://doi.org/10.14573/altex.2009.2.83

    Article  PubMed  Google Scholar 

  25. Wang S, Wang H, Guo H, Kang L, Gao X, Hu L (2011) Neuroprotection of Scutellarin is mediated by inhibition of microglial inflammatory activation. Neuroscience 185:150–160. https://doi.org/10.1016/j.neuroscience.2011.04.005

    Article  CAS  PubMed  Google Scholar 

  26. Pinteaux E, Parker LC, Rothwell NJ, Luheshi GN (2002) Expression of interleukin-1 receptors and their role in interleukin-1 actions in murine microglial cells. J Neurochem 83:754–763. https://doi.org/10.1046/j.1471-4159.2002.01184.x

    Article  CAS  PubMed  Google Scholar 

  27. Moon DO, Park SY, Lee KJ, Heo MS, Kim KC, Kim MO, Lee JD, Choi YH et al (2007) Bee venom and melittin reduce proinflammatory mediators in lipopolysaccharide-stimulated BV2 microglia. Int Immunopharmacol 7:1092–10101. https://doi.org/10.1016/j.intimp.2007.04.005

    Article  CAS  PubMed  Google Scholar 

  28. Elkahloun AG, Hafko R, Saavedra JM (2016) An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease. Alzheimers Res Ther 8:5. https://doi.org/10.1186/s13195-015-0167-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550. https://doi.org/10.1073/pnas.0506580102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jöhren O, Saavedra JM (1996) Expression of AT1A and AT1B angiotensin II receptor messenger RNA in forebrain of 2-wk-old rats. Am J Phys 271(1 Pt 1):E104–E112. https://doi.org/10.1152/ajpendo.1996.271.1.E104

    Article  Google Scholar 

  31. Miyoshi M, Miyano K, Moriyama N, Taniguchi M, Watanabe T (2008) Angiotensin type 1 receptor antagonist inhibits lipopolysaccharide-induced stimulation of rat microglial cells by suppressing nuclear factor kappaB and activator protein-1 activation. Eur J Neurosci 27:343–351. https://doi.org/10.1111/j.1460-9568.2007.06014.x

    Article  PubMed  Google Scholar 

  32. Li JJ, Lu J, Kaur C, Sivakumar V, Wu CY, Ling EA (2009) Expression of angiotensin II and its receptors in the normal and hypoxic amoeboid microglial cells and murine BV-2 cells. Neuroscience 158:1488–1499. https://doi.org/10.1016/j.neuroscience.2008.11.046

    Article  CAS  PubMed  Google Scholar 

  33. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947. https://doi.org/10.1523/JNEUROSCI.1860-14.2014 Supplemental materials at http://web.stanford.edu/group/barres_lab/brain_rnaseq.html

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pang T, Benicky J, Wang J, Orecna M, Sanchez-Lemus E, Saavedra JM (2012a) Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes. J Hypertens 30:87–96. https://doi.org/10.1097/HJH.0b013e32834dde5f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JCM, Sajti E, Jaeger BN, O'Connor C, Fitzpatrick C, Pasillas MP, Pena M, Adair A, Gonda DD, Levy ML, Ransohoff RM, Gage FH, Glass CK (2017) An environment-dependent transcriptional network specifies human microglia identity. Science 356(6344). https://doi.org/10.1126/science.aal3222.

    Article  Google Scholar 

  36. Ha YM, Park EJ, Kang YJ, Park SW, Kim HJ, Chang KC (2014) Valsartan independent of AT1 receptor inhibits tissue factor, TLR-2 and -4 expression by regulation of Egr-1 through activation of AMPK in diabetic conditions. J Cell Mol Med 18:2031–2043. https://doi.org/10.1111/jcmm.12354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yamamoto K, Ohishi M, Ho C, Kurtz TW, Rakugi H (2009) Telmisartan-induced inhibition of vascular cell proliferation beyond angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma activation. Hypertension 54:1353–1359. https://doi.org/10.1161/HYPERTENSIONAHA.109.138750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang Y, Huang Y, Xu Y, Ruan W, Wang H, Zhang Y, Saavedra JM, Zhang L et al (2018) A dual AMPK/Nrf2 activator reduces brain inflammation after stroke by enhancing microglia M2 polarization. Antioxid Redox Signal 28:141–163. https://doi.org/10.1089/ars.2017.7003

    Article  CAS  PubMed  Google Scholar 

  39. Leong DS, Terrón JA, Falcón-Neri A, Armando I, Ito T, Jöhren O, Tonelli LH, Hoe KL et al (2002) Restraint stress modulates brain, pituitary and adrenal expression of angiotensin II AT(1A), AT(1B) and AT(2) receptors. Neuroendocrinology 75:227–240. https://doi.org/10.1159/000054714

    Article  CAS  PubMed  Google Scholar 

  40. Kitamura Y, Taniguchi T, Kimura H, Nomura Y, Gebicke-Haerter PJ (2000) Interleukin-4-inhibited mRNA expression in mixed rat glial and in isolated microglial cultures. J Neuroimmunol 106:95–104

    Article  CAS  Google Scholar 

  41. Choi MJ, Lee EJ, Park JS, Kim SN, Park EM, Kim HS (2017) Anti-inflammatory mechanism of galangin in lipopolysaccharide-stimulated microglia: Critical role of PPAR-γ signaling pathway. Biochem Pharmacol 144:120–131. https://doi.org/10.1016/j.bcp.2017.07.021

    Article  CAS  PubMed  Google Scholar 

  42. Han Q, Yuan Q, Meng X, Huo J, Bao Y, Xie G (2017) 6-Shogaol attenuates LPS-induced inflammation in BV2 microglia cells by activating PPAR-γ. Oncotarget 8:42001–42006. https://doi.org/10.18632/oncotarget.16719

    Article  PubMed  PubMed Central  Google Scholar 

  43. Erbe DV, Gartrell K, Zhang YL, Suri V, Kirincich SJ, Will S, Perreault M, Wang S et al (2006) Molecular activation of PPARgamma by angiotensin II type 1-receptor antagonists. Vasc Pharmacol 45:154–162. https://doi.org/10.1016/j.vph.2006.05.002

    Article  CAS  Google Scholar 

  44. Iwashita M, Nakatsu Y, Sakoda H, Fujishiro M, Kushiyama A, Fukushima T, Kumamoto S, Shinjo T et al (2013) Valsartan restores inflammatory response by macrophages in adipose and hepatic tissues of LPS-infused mice. Adipocyte 2:28–32. https://doi.org/10.4161/adip.21837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cekanova M, Yuan JS, Li X, Kim K, Baek SJ (2008) Gene alterations by peroxisome proliferator-activated receptor gamma agonists in human colorectal cancer cells. Int J Oncol 32:809–819

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27:229–237

    Article  CAS  Google Scholar 

  47. Romano P, Manniello A, Aresu O, Armento M, Cesaro M, Parodi B (2009) Cell line data base: structure and recent improvements towards molecular authentication of human cell lines. Nucleic Acids Res 37:D925–D932. https://doi.org/10.1093/nar/gkn730

    Article  CAS  PubMed  Google Scholar 

  48. Sato S, Rancourt A, Sato Y, Satoh MS (2016) Single-cell lineage tracking analysis reveals that an established cell line comprises putative cancer stem cells and their heterogeneous progeny. Sci Rep 6:23328. https://doi.org/10.1038/srep23328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Salvi V, Sozio F, Sozzani S, Del Prete A (2017) Role of atypical chemokine receptors in microglial activation and polarization. Front Aging Neurosci 9:148. https://doi.org/10.3389/fnagi.2017.00148 eCollection 2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ham JE, Oh EK, Kim DH, Choi SH (2015) Differential expression profiles and roles of inducible DUSPs and ERK1/2-specific constitutive DUSP6 and DUSP7 in microglia. Biochem Biophys Res Commun 467:254–260. https://doi.org/10.1016/j.bbrc.2015.09.180

    Article  CAS  PubMed  Google Scholar 

  51. De I, Nikodemova M, Steffen MD, Sokn E, Maklakova VI, Watters JJ, Collier LS (2014) CSF1 overexpression has pleiotropic effects on microglia in vivo. Glia 62:1955–1967. https://doi.org/10.1002/glia.22717

    Article  PubMed  PubMed Central  Google Scholar 

  52. Desplats P, Dumaop W, Smith D, Adame A, Everall I, Letendre S, Ellis R, Cherner M et al (2013) Molecular and pathologic insights from latent HIV-1 infection in the human brain. Neurology 80:1415–1423. https://doi.org/10.1212/WNL.0b013e31828c2e9e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Khoshnam SE, Winlow W, Farbood Y, Moghaddam HF, Farzaneh M (2017) Emerging roles of microRNAs in ischemic stroke: as possible therapeutic agents. J Stroke 19:166–187. https://doi.org/10.5853/jos.2016.01368

    Article  PubMed  PubMed Central  Google Scholar 

  54. Truettner JS, Motti D, Dietrich WD (2013) MicroRNA overexpression increases cortical neuronal vulnerability to injury. Brain Res 1533:122–130. https://doi.org/10.1016/j.brainres.2013.08.011

    Article  CAS  PubMed  Google Scholar 

  55. Li F, Wei G, Bai Y, Li Y, Huang F, Lin J, Hou Q, Deng R et al (2015a) MicroRNA-574 is involved in cognitive impairment in 5-month-old APP/PS1 mice through regulation of neuritin. Brain Res 1627:177–188. https://doi.org/10.1016/j.brainres.2015.09.022

    Article  CAS  PubMed  Google Scholar 

  56. Leisner TM, Freeman TC, Black JL, Parise LV (2016) CIB1: a small protein with big ambitions. FASEB J 30:2640–2650. https://doi.org/10.1096/fj.201500073R

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pisetsky DS (2013) Immune activation by histones: plusses and minuses in inflammation. Eur J Immunol 43:3163–3166. https://doi.org/10.1002/eji.201344175

    Article  CAS  PubMed  Google Scholar 

  58. Hooper LV, Stappenbeck TS, Hong CV, Gordon JI (2003) Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat Immunol 4:269–273. https://doi.org/10.1038/ni888

    Article  CAS  PubMed  Google Scholar 

  59. Palmieri F (2013) The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol Asp Med 34:465–484. https://doi.org/10.1016/j.mam.2012.05.005

    Article  CAS  Google Scholar 

  60. Pereg Y, Liu BY, O'Rourke KM, Sagolla M, Dey A, Komuves L, French DM, Dixit VM (2010) Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A. Nat Cell Biol 12:400–406. https://doi.org/10.1038/ncb2041

    Article  CAS  PubMed  Google Scholar 

  61. Barger JL, Vann JM, Cray NL, Pugh TD, Mastaloudis A, Hester SN, Wood SM, Newton MA et al (2017) Identification of tissue-specific transcriptional markers of caloric restriction in the mouse and their use to evaluate caloric restriction mimetics. Aging Cell 16:750–760. https://doi.org/10.1111/acel.12608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. de Cavanagh EM, Inserra F, Ferder L (2015) Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309:H15–H44. https://doi.org/10.1152/ajpheart.00459.2014

    Article  CAS  PubMed  Google Scholar 

  63. Blom T, Schmiedt M-L, Wong AM, Kyttala A, Soronen J, Jauhiainen M, Tyynelä J, Cooper JD et al (2013) Exacerbated neuronal ceroid lipofuscinosis phenotype in Cln1/5 double-knockout mice. Dis Model Mech 6:342–357. https://doi.org/10.1242/dmm.010140

    Article  CAS  PubMed  Google Scholar 

  64. Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649–665. https://doi.org/10.1111/bph.13139

    Article  CAS  PubMed  Google Scholar 

  65. Christian R, Raetz H, Whitfield C (2002) Lipopolysaccharide endotoxins. Annu Rev Biochem 71:635–700. https://doi.org/10.1146/annurev.biochem.71.110601.135414

    Article  CAS  Google Scholar 

  66. Taniguchi K, Karin M (2014) IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol 26:54–74. https://doi.org/10.1016/j.smim.2014.01.001

    Article  CAS  PubMed  Google Scholar 

  67. Nelson DE, Ihekwaba AE, Elliott M, Johnson JR, Gibney CA, Foreman BE, Nelson G et al (2004) Oscillations in NF-kappaB signaling control the dynamics of gene expression. Science 306:704–708. https://doi.org/10.1126/science.1099962

    Article  CAS  PubMed  Google Scholar 

  68. Croft M, Duan W, Choi H, Eun SY, Madireddi S, Mehta A (2012) TNF superfamily in inflammatory disease: translating basic insights. Trends Immunol 33:144–152. https://doi.org/10.1016/j.it.2011.10.004

    Article  CAS  PubMed  Google Scholar 

  69. Marques-Rocha JL, Samblas M, Milagro FI, Bressan J, Martínez JA, Marti A (2015) Noncoding RNAs, cytokines, and inflammation-related diseases. FASEB J 29:3595–3611. https://doi.org/10.1096/fj.14-260323

    Article  CAS  PubMed  Google Scholar 

  70. Clarner T, Janssen K, Nellessen L, Stangel M, Skripuletz T, Krauspe B, Hess FM, Denecke B et al (2015) CXCL10 triggers early microglial activation in the cuprizone model. J Immunol 194:3400–3413. https://doi.org/10.4049/jimmunol.1401459

    Article  CAS  PubMed  Google Scholar 

  71. Daulatzai MA (2015) Olfactory dysfunction: its early temporal relationship and neural correlates in the pathogenesis of Alzheimer’s disease. J Neural Transm (Vienna) 122:1475–1497. https://doi.org/10.1007/s00702-015-1404-6

    Article  CAS  Google Scholar 

  72. Ferrer I, Garcia-Esparcia P, Carmona M, Carro E, Aronica E, Kovacs GG, Grison A, Gustincich S (2016) Olfactory receptors in non-chemosensory organs: the nervous system in health and disease. Front Aging Neurosci 8:163. https://doi.org/10.3389/fnagi.2016.00163 eCollection 2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Han JA, Kim JY, Kim JI (2014) Analysis of gene expression in cyclooxygenase-2-overexpressed human osteosarcoma cell lines. Genomics Inform 12:247–253. https://doi.org/10.5808/GI.2014.12.4.247

    Article  PubMed  PubMed Central  Google Scholar 

  74. Ampofo E, Schmitt BM, Menger MD, Laschke M.W (2017) The regulatory mechanisms of NG2/CSPG4 expression. Cell Mol Biol Lett 22:4. https://doi.org/10.1186/s11658-017-0035-3. eCollection 2017.

  75. Stepanov GA, Filippova JA, Komissarov AB, Kuligina EV, Richter VA, Semenov DV (2015) Regulatory role of small nucleolar RNAs in human diseases. Biomed Res Int 2015:206849. https://doi.org/10.1155/2015/206849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kim W, Kim JE (2013) SIRT7 an emerging sirtuin: deciphering newer roles. J Physiol Pharmacol 64:531–534

    Article  CAS  Google Scholar 

  77. Jiang T, Zhang YD, Gao Q, Ou Z, Gong PY, Shi JQ, Wu L, Zhou JS (2018) TREM2 ameliorates neuronal tau pathology through suppression of microglial inflammatory response. Inflammation. https://doi.org/10.1007/s10753-018-0735-5

    Article  CAS  Google Scholar 

  78. Wang J, Si Y, Wu C, Sun L, Ma Y, Ge A, Li B (2012) Lipopolysaccharide promotes lipid accumulation in human adventitial fibroblasts via TLR4-NF-κB pathway. Lipids Health Dis 11:139. https://doi.org/10.1186/1476-511X-11-139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bode JG, Ehlting C, Häussinger D (2012) The macrophage response towards LPS and its control through the p38(MAPK)-STAT3 axis. Cell Signal 24:1185–1194. https://doi.org/10.1016/j.cellsig.2012.01.018

    Article  CAS  PubMed  Google Scholar 

  80. Poujol F, Monneret G, Pachot A, Textoris J, Venet F (2015) Altered T lymphocyte proliferation upon lipopolysaccharide challenge ex vivo. PLoS One 10:e0144375. https://doi.org/10.1371/journal.pone.0144375 eCollection 2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Abella V, Scotece M, Conde J, Gómez R, Lois A, Pino J, Gómez-Reino JJ, Lago F et al (2015) The potential of lipocalin-2/NGAL as biomarker for inflammatory and metabolic diseases. Biomarkers 20:565–571. https://doi.org/10.3109/1354750X.2015.1123354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Khalil M, Renner A, Langkammer C, Enzinger C, Ropele S, Stojakovic T, Scharnagl H, Bachmaier G et al (2016) Cerebrospinal fluid lipocalin 2 in patients with clinically isolated syndromes and early multiple sclerosis. Mult Scler 22:1560–1568. https://doi.org/10.1177/1352458515624560

    Article  CAS  PubMed  Google Scholar 

  83. Bhatelia K, Singh K, Singh R (2014) TLRs: linking inflammation and breast cancer. Cell Signal 26:2350–2357. https://doi.org/10.1016/j.cellsig.2014.07.035

    Article  CAS  PubMed  Google Scholar 

  84. Cuenda A, Rousseau S (2007) p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 1773:1358–1375. https://doi.org/10.1016/j.bbamcr.2007.03.010

    Article  CAS  PubMed  Google Scholar 

  85. Ueda K, Nakahara T, Akanuma K, Mori A, Sakamoto K, Ishii K (2013) Differential effects of LY294002 and wortmannin on neurons and vascular endothelial cells in the rat retina. Pharmacol Rep 65:854–862

    Article  CAS  Google Scholar 

  86. Ong Q, Guo S, Zhang K, Cui B (2015) U0126 protects cells against oxidative stress independent of its function as a MEK inhibitor. ACS Chem Neurosci 6:130–137. https://doi.org/10.1021/cn500288n

    Article  CAS  PubMed  Google Scholar 

  87. Sandoval-Hernández AG, Buitrago L, Moreno H, Cardona-Gómez GP, Arboleda G (2015) Role of liver X receptor in AD pathophysiology. PLoS One 10(12):e0145467. https://doi.org/10.1371/journal.pone.0145467 eCollection 2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yu HM, Zhao YM, Luo XG, Feng Y, Ren Y, Shang H, He ZY, Luo XM et al (2012) Repeated lipopolysaccharide stimulation induces cellular senescence in BV2 cells. Neuroimmunomodulation 19:131–136. https://doi.org/10.1159/000330254

    Article  CAS  PubMed  Google Scholar 

  89. Atsumi T, Singh R, Sabharwal L, Bando H, Meng J, Arima Y, Yamada M, Harada M et al (2014) Inflammation amplifier, a new paradigm in cancer biology. Cancer Res 74:8–14. https://doi.org/10.1158/0008-5472.CAN-13-2322

    Article  CAS  PubMed  Google Scholar 

  90. Diakos CI, Charles KA, McMillan DC, Clarke SJ (2014) Cancer-related inflammation and treatment effectiveness. Lancet Oncol 15:e493–e503. https://doi.org/10.1016/S1470-2045(14)70263-3

    Article  PubMed  Google Scholar 

  91. Banks WA, Gray AM, Erickson MA, Salameh TS, Damodarasamy M, Sheibani N, Meabon JS, Wing EE et al (2015) Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. J Neuroinflammation 12:223. https://doi.org/10.1186/s12974-015-0434-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhao D, Zhuang N, Ding Y, Kang Y, Shi L (2016) MiR-221 activates the NF-κB pathway by targeting A20. Biochem Biophys Res Commun 472:11–18. https://doi.org/10.1016/j.bbrc.2015.11.009

    Article  CAS  PubMed  Google Scholar 

  93. Huang Y, Chen J, Zhou Y, Tang S, Li J, Yu X, Mo Y, Wu Y et al (2016) Circulating miR155 expression level is positive with blood pressure parameters: potential markers of target-organ damage. Clin Exp Hypertens 38:331–336. https://doi.org/10.3109/10641963.2015.1116551

    Article  CAS  PubMed  Google Scholar 

  94. Guo S, Messmer-Blust AF, Wu J, Song X, Philbrick MJ, Shie J-L, Rana JS, Li J (2014) Role of A20 in cIAP-2 protection against tumor necrosis factor α (TNF-α)-mediated apoptosis in endothelial cells. Int J Mol Sci 15:3816–3833. https://doi.org/10.3390/ijms15033816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Raetz CR, Whitfield C (2002) Lipopolysaccharide endotoxins. Annu Rev Biochem 71:635–700. https://doi.org/10.1146/annurev.biochem.71.110601.135414

    Article  CAS  PubMed  Google Scholar 

  96. Lemarchant S, Pruvost M, Montaner J, Emery E, Vivien D, Kanninen K, Koistinaho J (2013) ADAMTS proteoglycanases in the physiological and pathological central nervous system. J Neuroinflammation 10:133. https://doi.org/10.1186/1742-2094-10-133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wang G, Huang Y, Wang LL, Zhang YF, Xu J, Zhou Y, Lourenco GF, Zhang B et al (2016) MicroRNA-146a suppresses ROCK1 allowing hyperphosphorylation of tau in Alzheimer’s disease. Sci Rep 6:26697. https://doi.org/10.1038/srep26697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ansoleaga B, Garcia-Esparcia P, Llorens F, Moreno J, Aso E, Ferrer I (2013) Dysregulation of brain olfactory and taste receptors in AD, PSP and CJD, and AD-related model. Neuroscience 248:369–382. https://doi.org/10.1016/j.neuroscience.2013.06.034

    Article  CAS  PubMed  Google Scholar 

  99. Lupton MK, Proitsi P, Lin K, Hamilton G, Daniilidou M, Tsolaki M, Powell JF (2014) The role of ABCA1 gene sequence variants on risk of Alzheimer’s disease. J Alzheimers Dis 38:897–906. https://doi.org/10.3233/JAD-131121

    Article  CAS  PubMed  Google Scholar 

  100. Sabirzhanov B, Stoica BA, Zhao Z, Loane DJ, Wu J, Dorsey SG, Faden AI (2016) miR-711 upregulation induces neuronal cell death after traumatic brain injury. Cell Death Differ 23:654–668. https://doi.org/10.1038/cdd.2015.132

    Article  CAS  PubMed  Google Scholar 

  101. Garrigan E, Belkin NS, Seydel F, Han Z, Carter J, McDuffie M, Morel L, Peck AB et al (2015) Csf2 and Ptgs2 epigenetic dysregulation in diabetes-prone Bicongenic B6.NODC11bxC1tb mice. Genet Epigenet 7:5–17. https://doi.org/10.4137/GEG.S29696 eCollection 2015

    Article  PubMed  PubMed Central  Google Scholar 

  102. Bensellam M, Montgomery MK, Luzuriaga J, Chan JY, Laybutt DR (2015) Inhibitor of differentiation proteins protect against oxidative stress by regulating the antioxidant-mitochondrial response in mouse beta cells. Diabetologia 58:758–770. https://doi.org/10.1007/s00125-015-3503-1

    Article  CAS  PubMed  Google Scholar 

  103. Lee MS, Kim B, Oh GT, Kim YJ (2013) OASL1 inhibits translation of the type I interferon-regulating transcription factor IRF7. Nat Immunol 14:346–355. https://doi.org/10.1038/ni.2535 Erratum in: Nat Immunol. 2013;14:355. Nat Immunol. 2013;14:877

    Article  CAS  PubMed  Google Scholar 

  104. Miao Y, Cui L, Chen Z, Zhang L (2016) Gene expression profiling of DMU-212-induced apoptosis and anti-angiogenesis in vascular endothelial cells. Pharm Biol 54:660–666. https://doi.org/10.3109/13880209.2015.1071414

    Article  CAS  PubMed  Google Scholar 

  105. Nair S, Rein A (2014) Antiretroviral restriction factors in mice. Virus Res 193:130–134. https://doi.org/10.1016/j.virusres.2014.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251. https://doi.org/10.1126/science.285.5425.248

    Article  CAS  PubMed  Google Scholar 

  107. Bao XM, He Q, Wang Y, Huang ZH, Yuan ZQ (2017) The roles and mechanisms of the Hippo/YAP signaling pathway in the nervous system. Yi Chuan 39:630–641. https://doi.org/10.16288/j.yczz.17-069

    Article  PubMed  Google Scholar 

  108. Harvey KF, Zhang X, Thomas DM (2013) The hippo pathway and human cancer. Nat Rev Cancer 13:246–257. https://doi.org/10.1038/nrc3458

    Article  CAS  PubMed  Google Scholar 

  109. Patel RK, Prasad N, Kuwar R, Haldar D, Abdul-Muneer PM (2017) Transforming growth factor-beta 1 signaling regulates neuroinflammation and apoptosis in mild traumatic brain injury. Brain Behav Immun 64:244–258. https://doi.org/10.1016/j.bbi.2017.04.012

    Article  CAS  PubMed  Google Scholar 

  110. Heyninck K, De Valck D, Vanden Berghe W, Van Criekinge W, Contreras R, Fiers W, Haegeman G, Beyaert R (1999) The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN. J Cell Biol 145:1471–1482

    Article  CAS  Google Scholar 

  111. Rutkowski DT, Kaufman RJ (2003) All roads lead to ATF4. Dev Cell 4:442–444. https://doi.org/10.1016/S1534-5807(03)00100-X

    Article  CAS  PubMed  Google Scholar 

  112. Guleria RS, Choudhary R, Tanaka T, Baker KM, Pan J (2011) Retinoic acid receptor-mediated signaling protects cardiomyocytes from induced apoptosis: Role of the renin-angiotensin system. J Cell Physiol 226:1292–1307. https://doi.org/10.1002/jcp.22457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zhang H, Taylor WR, Joseph G, Caracciolo V, Gonzales DM, Sidell N, Seli E, Blackshear PJ et al (2013) mRNA-binding protein ZFP36 is expressed in atherosclerotic lesions and reduces inflammation in aortic endothelial cells. Arterioscler Thromb Vasc Biol 33:1212–1220. https://doi.org/10.1161/ATVBAHA.113.301496

    Article  CAS  PubMed  Google Scholar 

  114. Heffron DS, Mandell JW (2005) Opposing roles of ERK and p38 MAP kinases in FGF2-induced astroglial process extension. Mol Cell Neurosci 28:779–790. https://doi.org/10.1016/j.mcn.2004.12.010

    Article  CAS  PubMed  Google Scholar 

  115. Jayasooriya RG, Lee KT, Kang CH, Dilshara MG, Lee HJ, Choi YH, Choi IW, Kim GY (2014) Isobutyrylshikonin inhibits lipopolysaccharide-induced nitric oxide and prostaglandin E2 production in BV2 microglial cells by suppressing the PI3K/Akt-mediated nuclear transcription factor-κB pathway. Nutr Res 34:1111–1119. https://doi.org/10.1016/j.nutres.2014.10.002

    Article  CAS  PubMed  Google Scholar 

  116. Pang T, Wang J, Benicky J, Sánchez-Lemus E, Saavedra JM (2012b) Telmisartan directly ameliorates the neuronal inflammatory response to IL-1β partly through the JNK/c-Jun and NADPH oxidase pathways. J Neuroinflammation 102. https://doi.org/10.1186/1742-2094-9-102

  117. Antipova AA, Stockwell BR, Golub TR (2008) Gene expression-based screening for inhibitors of PDGFR signaling. Genome Biol 9:R47. https://doi.org/10.1186/gb-2008-9-3-r47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Berk M, Malhi GS, Gray LJ, Dean OM (2013) The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci 34:167–177. https://doi.org/10.1016/j.tips.2013.01.001

    Article  CAS  PubMed  Google Scholar 

  119. Zhang F, Sun D, Chen J, Guan N, Huo X, Xi H (2015) Simvastatin attenuates angiotensin II-induced inflammation and oxidative stress in human mesangial cells. Mol Med Rep 11:1246–1251. https://doi.org/10.3892/mmr.2014.2871

    Article  CAS  PubMed  Google Scholar 

  120. Yang W, Chauhan A, Mehta S, Mehta P, Gu F, Chauhan V (2014) Trichostatin A increases the levels of plasma gelsolin and amyloid beta-protein in a transgenic mouse model of Alzheimer’s disease. Life Sci 99:31–36. https://doi.org/10.1016/j.lfs.2014.01.064

    Article  CAS  PubMed  Google Scholar 

  121. De Souza C, Chatterji BP (2015) HDAC inhibitors as novel anti-cancer therapeutics. Recent Pat Anticancer Drug Discov 10:145–162. https://doi.org/10.2174/1574892810666150317144511

    Article  CAS  PubMed  Google Scholar 

  122. Doan NT, Paulsen ES, Sehgal P, Møller JV, Nissen P, Denmeade SR, Isaacs JT, Dionne CA (2015) Targeting thapsigargin towards tumors. Steroids 97:2–7. https://doi.org/10.1016/j.steroids.2014.07.009

    Article  CAS  PubMed  Google Scholar 

  123. Seargent JM, Yates EA, Gill JH (2004) GW9662, a potent antagonist of PPARgamma, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARgamma agonist rosiglitazone, independently of PPARgamma activation. Br J Pharmacol 143:933–937. https://doi.org/10.1038/sj.bjp.0705973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wong SB, Cheng SJ, Hung WC, Lee WT, Min MY (2015) Rosiglitazone suppresses in vitro seizures in hippocampal slice by inhibiting presynaptic glutamate release in a model of temporal lobe epilepsy. PLoS One 10(12):e0144806. https://doi.org/10.1371/journal.pone.0144806 eCollection 2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Allam R, Kumar SV, Darisipudi MN, Anders HJ (2014) Extracellular histones in tissue injury and inflammation. J Mol Med (Berl) 92:465–472. https://doi.org/10.1007/s00109-014-1148-z

    Article  CAS  Google Scholar 

  126. Vardabasso C, Hasson D, Ratnakumar K, Chung CY, Duarte LF, Bernstein E (2014) Histone variants: emerging players in cancer biology. Cell Mol Life Sci 71:379–404. https://doi.org/10.1007/s00018-013-1343-z

    Article  CAS  PubMed  Google Scholar 

  127. Love S, Miners JS (2016) Cerebrovascular disease in ageing and Alzheimer’s disease. Acta Neuropathol 131:645–658. https://doi.org/10.1007/s00401-015-1522-0

    Article  CAS  PubMed  Google Scholar 

  128. O'Connor T, Borsig L, Heikenwalder M (2015) CCL2-CCR2 signaling in disease pathogenesis. Endocr Metab Immune Disord Drug Targets 15:105–118. https://doi.org/10.2174/1871530315666150316120920

    Article  CAS  PubMed  Google Scholar 

  129. Cho KA, Kang PB (2015) PLIN2 inhibits insulin-induced glucose uptake in myoblasts through the activation of the NLRP3 inflammasome. Int J Mol Med 36:839–844. https://doi.org/10.3892/ijmm.2015.2276

    Article  CAS  PubMed  Google Scholar 

  130. Naito Y, Takagi T, Higashimura Y (2014) Heme oxygenase-1 and anti-inflammatory M2 macrophages. Arch Biochem Biophys 564:83–88. https://doi.org/10.1016/j.abb.2014.09.005

    Article  CAS  PubMed  Google Scholar 

  131. Yu S, Wang X, Lei S, Chen X, Liu Y, Zhou Y, Zhou Y, Wu J, Zhao Y (2015) Sulfiredoxin-1 protects primary cultured astrocytes from ischemia-induced damage. Neurochem Int 19-27. https://doi.org/10.1016/j.neuint.2015.01.005.

    Article  CAS  Google Scholar 

  132. Riggin CH Jr, Pitha PM (1982) Methylation and a polymorphic restriction site adjacent to human beta-interferon gene. DNA 1:267–271

    Article  CAS  Google Scholar 

  133. Li J, Yang J, Lu YW, Wu S, Wang MR, Zhu JM (2015b) Possible role of staphylococcal enterotoxin B in the pathogenesis of autoimmune diseases. Viral Immunol 28:354–359. https://doi.org/10.1089/vim.2015.0017

    Article  CAS  PubMed  Google Scholar 

  134. Urra FA, Araya-Maturana R (2017) Targeting metastasis with snake toxins: molecular mechanisms. Toxins (Basel) 9. https://doi.org/10.3390/toxins9120390.

    Article  Google Scholar 

  135. Matsui T, Ingelsson M, Fukumoto H, Ramasamy K, Kowa H, Frosch MP, Irizarry MC, Hyman BT (2007) Expression of APP pathway mRNAs and proteins in Alzheimer’s disease. Brain Res 1161:116–123. https://doi.org/10.1016/j.brainres.2007.05.050

    Article  CAS  PubMed  Google Scholar 

  136. Liu Z, Chen HQ, Huang Y, Qiu YH, Peng YP (2016) Transforming growth factor-β1 acts via TβR-I on microglia to protect against MPP(+)-induced dopaminergic neuronal loss. Brain Behav Immun 51:131–143. https://doi.org/10.1016/j.bbi.2015.08.006

    Article  CAS  PubMed  Google Scholar 

  137. Yanamandra M, Mitra S, Giri A (2015) Development and application of PI3K assays for novel drug discovery. Expert Opin Drug Discov 10:171–186. https://doi.org/10.1517/17460441.2015.997205

    Article  CAS  PubMed  Google Scholar 

  138. Figarska SM, Vonk JM, Boezen HM (2014) NFE2L2 polymorphisms, mortality, and metabolism in the general population. Physiol Genomics 46:411–417. https://doi.org/10.1152/physiolgenomics.00178.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. von Otter M, Bergström P, Quattrone A, De Marco EV, Annesi G, Söderkvist P, Wettinger SB, Drozdzik M et al (2014) Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson’s disease—a multicenter study. BMC Med Genet 15:131. https://doi.org/10.1186/s12881-014-0131-4

    Article  CAS  Google Scholar 

  140. Palma-Gudiel H, Córdova-Palomera A, Leza JC, Fañanás L (2015) Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: a critical review. Neurosci Biobehav Rev 55:520–535. https://doi.org/10.1016/j.neubiorev.2015.05.016

    Article  CAS  PubMed  Google Scholar 

  141. Kulkarni SS, Cantó C (2015) The molecular targets of resveratrol. Biochim Biophys Acta 1852:1114–1123. https://doi.org/10.1016/j.bbadis.2014.10.005

    Article  CAS  PubMed  Google Scholar 

  142. Gupta SC, Patchva S, Aggarwal BB (2013) Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J 15:195–218. https://doi.org/10.1208/s12248-012-9432-8

    Article  CAS  PubMed  Google Scholar 

  143. Deguchi A (2015) Curcumin targets in inflammation and cancer. Endocr Metab Immune Disord Drug Targets 15:88–96. https://doi.org/10.2174/1871530315666150316120

    Article  CAS  PubMed  Google Scholar 

  144. Namura S, Iihara K, Takami S, Nagata I, Kikuchi H, Matsushita K, Moskowitz MA, Bonventre JV et al (2001) Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia. Proc Natl Acad Sci U S A 98:11569–11574. https://doi.org/10.1073/pnas.181213498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wang X, Wang H, Xu L, Rozanski DJ, Sugawara T, Chan PH, Trzaskos JM, Feuerstein GZ (2003) Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: exploration of potential mechanism associated with apoptosis. J Pharmacol Exp Ther 304:172–178. https://doi.org/10.1124/jpet.102.040246

    Article  CAS  PubMed  Google Scholar 

  146. Freilich RW, Woodbury ME, Ikezu T (2013) Integrated expression profiles of mRNA and miRNA in polarized primary murine microglia. PLoS One 8:e79416. https://doi.org/10.1371/journal.pone.0079416 eCollection 2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Chen G, Nie S, Han C, Ma K, Xu Y, Zhang Z, Papa SM, Cao X (2017) Antidyskinetic effects of MEK inhibitor are associated with multiple neurochemical alterations in the striatum of hemiparkinsonian rats. Front Neurosci 11:112. https://doi.org/10.3389/finns.2017.00112 eCollection 2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Creighton CJ, Hilger AM, Murthy S, Rae JM, Chinnaiyan AM, El-Ashry D (2006) Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors. Cancer Res 66:3903–3911. https://doi.org/10.1158/0008-5472.CAN-05-4363

    Article  CAS  PubMed  Google Scholar 

  149. Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D (2015) Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation 12:114. https://doi.org/10.1186/s12974-015-0332-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Ahn KO, Lim SW, Li C, Yang HJ, Ghee JY, Kim JY, Kim SH, Kim J et al (2007) Influence of angiotensin II on expression of toll-like receptor 2 and maturation of dendritic cells in chronic cyclosporine nephropathy. Transplantation 83:938–947. https://doi.org/10.1097/01.tp.0000258589.39006.94132

    Article  CAS  PubMed  Google Scholar 

  151. Barakat W, Safwet N, El-Maraghy NN, Zakaria MN (2014) Candesartan and glycyrrhizin ameliorate ischemic brain damage through downregulation of the TLR signaling cascade. Eur J Pharmacol 724:43–50. https://doi.org/10.1016/j.ejphar.2013.12.032

    Article  CAS  PubMed  Google Scholar 

  152. Biancardi VC, Stranahan AM, Krause EG, de Kloet AD, Stern JE (2016) Cross talk between AT1 receptors and toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus. Am J Physiol Heart Circ Physiol 310:H404–H415. https://doi.org/10.1152/ajpheart.00247.2015

    Article  PubMed  Google Scholar 

  153. Cheng XW, Song H, Sasaki T, Hu L, Inoue A, Bando YK, Shi GP, Kuzuya M et al (2011) Angiotensin type 1 receptor blocker reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Hypertension 57:981–989. https://doi.org/10.1161/HYPERTENSIONAHA.110.168385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Rinaldi B, Di Filippo C, Capuano A, Donniacuo M, Sodano L, Ferraraccio F, Rossi F, D'Amico M (2012) Adiponectin elevation by telmisartan ameliorates ischaemic myocardium in Zucker diabetic fatty rats with metabolic syndrome. Diabetes Obes Metab 14:320–328. https://doi.org/10.1111/j.1463-1326.2011.01527.x

    Article  CAS  PubMed  Google Scholar 

  155. Dasu MR, Riosvelasco AC, Jialal I (2009) Candesartan inhibits toll-like receptor expression and activity both in vitro and in vivo. Atherosclerosis 202:76–83. https://doi.org/10.1016/j.atherosclerosis.2008.04.010

    Article  CAS  PubMed  Google Scholar 

  156. Yang J, Jiang H, Yang J, Ding JW, Chen LH, Li S, Zhang XD (2009) Valsartan preconditioning protects against myocardial ischemia-reperfusion injury through TLR4/NF-kappaB signaling pathway. Mol Cell Biochem 330:39–46. https://doi.org/10.1007/s11010-009-0098-1

    Article  CAS  PubMed  Google Scholar 

  157. Wang Y, Li Y, Shen Q, Li X, Lu J, Li X, Yin D, Peng Y (2014b) Valsartan blocked alcohol-induced, toll-like receptor 2 signaling-mediated inflammation in human vascular endothelial cells. Alcohol Clin Exp Res 38:2529–2540. https://doi.org/10.1111/acer.12532

    Article  CAS  PubMed  Google Scholar 

  158. Lv J, Jia R, Yang D, Zhu J, Ding G (2009) Candesartan attenuates angiotensin II-induced mesangial cell apoptosis via TLR4/MyD88 pathway. Biochem Biophys Res Commun 380:81–86. https://doi.org/10.1016/j.bbrc.2009.01.035

    Article  CAS  PubMed  Google Scholar 

  159. Saravanan PB, Shanmuganathan MV, Ramanathan M (2015) Telmisartan attenuated LPS-induced neuroinflammation in human IMR-32 neuronal cell line via SARM in AT1R independent mechanism. Life Sci 130:88–96. https://doi.org/10.1016/j.lfs.2015.03.005

    Article  CAS  PubMed  Google Scholar 

  160. Takahashi Y, Satoh M, Minami Y, Tabuchi T, Itoh T, Nakamura M (2010) Expression of miR-146a/b is associated with the toll-like receptor 4 signal in coronary artery disease: effect of renin-angiotensin system blockade and statins on miRNA-146a/b and toll-like receptor 4 levels. Clin Sci (Lond) 119:395–405. https://doi.org/10.1042/CS20100003

    Article  CAS  Google Scholar 

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Acknowledgements

AGE was supported by the National Human Genome Research Institute Intramural Program, National Institutes of Health.

YR was a research technician at the Department of Pharmacology and Physiology, Georgetown University Medical Center.

SA was supported by a scholarship from the government of the Kingdom of Saudi Arabia and by the Master in Physiology Program at Georgetown University Medical Center.

EW was a PhD student, Department of Pharmacology and Physiology, Georgetown University Medical Center.

JMS was supported by a GX4002-705 grant from Partners in Research, Georgetown University Medical Center.

Author information

Authors and Affiliations

  1. Microarray Core, Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Dr, MSC 4435, Bethesda, MD, 20892-4435, USA

    Abdel G. Elkahloun

  2. Laboratory of Neuroprotection, Department of Pharmacology and Physiology, Georgetown University Medical Center, SE402 Med/Dent, 3900 Reservoir Road, Washington, DC, 20057, USA

    Yara Rodriguez, Seham Alaiyed, Erin Wenzel & Juan M. Saavedra

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  1. Abdel G. Elkahloun
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  2. Yara Rodriguez
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  3. Seham Alaiyed
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  4. Erin Wenzel
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  5. Juan M. Saavedra
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Contributions

AE performed the microarrays, conducted and analyzed the genome wide study, interpreted the results, and contributed to writing the manuscript.

YR, SA and EW performed the cells culture and qPCR experiments, interpreted the results and contributed to writing the manuscript.

JMS conceived the project, supervised the cell culture and qPCR experiments, interpreted the results, and contributed to writing the manuscript.

Corresponding author

Correspondence to Juan M. Saavedra.

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The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplemental Fig. 1

Valsartan significantly reduces LPS-induced increase in IL-1β and IL-6 gene expression. A) Exposure to Valsartan (Val) 20 μM for 2 h significantly reduces the increase in IL-1β gene expression produced after 1 h of exposure to LPS (100 ng/ml). ANOVA F (3, 16) = 58.45, p < 0.0001. B) Exposure to Valsartan (Val) 20 μM for 2 h significantly reduces the increase in IL-6 gene expression produced after 1 h of exposure to LPS (100 ng/ml). ANOVA F (3, 16) = 83.36, p < 0.0001. Results are means ± SEM for three to five groups analyzed independently. Data were analyzed by one-way ANOVA with Newman-Keuls to correct for multiple comparisons. ****p < 0.0001 compared to DMSO; ####p < 0.0001 compared to Val; +p < 0.05 ++p < 0.01 compared to LPS. (PDF 1014 kb)

Supplemental Fig. 2

The PPARγ antagonist T0070907 eliminates the LPS-induced increase in IL-1β and IL6 cytokines gene expression. A) Exposure to the PPARγ antagonist T0070907 10 μM (T007) for 2 h eliminates the increase in IL-1β gene expression produced after 1 h of exposure to LPS (100 ng/ml). T0070907 effect reducing IL-1β gene expression after LPS treatment is stronger than the effect of 2-h pretreatment with Telmisartan (Telm) 10 μM. ANOVA F (6, 14) = 143.7, p < 0.0001. B) Exposure to the PPARγ antagonist T0070907 10 μM (T007) or to Telmisartan (Telm) 10 μM alone for 2 h eliminates the increase in IL-6 gene expression produced after 1 h of exposure to LPS (100 ng/ml). T0070907 potentiates the effect of Telmisartan reducing IL-6 gene expression. ANOVA F (6,14) =185.5, p < 0.0001 Results are means ± SEM for three to five groups analyzed independently. Data were analyzed by one-way ANOVA with Newman-Keuls to correct for multiple comparisons. ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05 compared to DMSO; ####p < 0.0001, ##p < 0.01, #p < 0.05 compared to Telm; ++++p < 0.0001, +++p < 0.001, +p < 0.05 compared to T007; $$p < 0.0001 compared to LPS; %%%p < 0.001, %%p < 0.01 compared to LPS + Telm; &p < 0.05 compared to T007 + LPS. (PDF 1237 kb)

Supplemental Table 1

BV-2 Cell Check. The Cell Check was performed by IDEXX BioResearch, Columbia, MO. The sample was confirmed to be of mouse origin and no mammalian interspecies contamination was detected. A genetic profile was generated for the sample by using a panel of STR markers for genotyping. NA in the table indicates that a genetic profile has not been previously established for this cell line. The profile generated for this sample can be used for comparison of samples in the future and should be included as a reference profile in publications. (DOCX 14 kb)

Supplemental Table 2

List of primers used for qPCR. AT1: Angiotensin II receptor AT1; PPARγ: Peroxisome proliferator-activated receptor gamma; IL-1β: Interleukin-1 beta; IL-6: Interleukin-6; TNFα: Tumor necrosis factor alpha; Iκβα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase. Primers for PPARɣ were purchased from IDT (Coralville, IO). All other primers were synthesized by BioServe (Beltsville, MD). (DOCX 15 kb)

Supplemental Table 3

Microarray data for all the 4 different comparisons. (DMSO+Telmisartan, DMSO+LPS, LPS + Telmisartan, LPS + Telmisartan+GW9662) with p-value, Fold Change and direction for all genes. Subsets of significantly differentially expressed genes, including statistical significance, fold change and direction, are presented in different spreadsheets in this order: all gene samples, upregulated by Telmisartan+DMSO, downregulated by Telmisartan+DMSO, 1) upregulated by LPS + DMSO, 2) downregulated by LPS + DMSO, 3) upregulated by Telmisartan+LPS, 4) downregulated by Telmisartan+LPS, 5) upregulated by Telmisartan+LPS + GW9662, 6) downregulated by Telmisartan+LPS + GW9662. Mouse gene symbols are based on the approved HUGO Gene Nomenclature Committee. Agtr1: AT1 receptor; Agtr1a: AT1A receptor; Agtr1b: AT1B receptor; Agtr2: AT2 receptor; Pparg: PPARγ. Tel: Telmisartan. GW: GW9662. An additional sheet has been added to present select genes expression values. (XLSX 4286 kb)

Supplemental Table 4

Microarray data of significantly differentially expressed genes between DMSO versus Telmisartan that are used for the IPA (Ingenuity Pathways Analysis). Different IPA outputs are presented in different spreadsheets: 1) list of genes upregulated or downregulated by Telmisartan, including statistical significance, fold change and direction, 2) Diseases and functions, 3) Upstream regulators, 4) Networks, 5) GSEA (Gene Set Enrichment Analysis) output for GSE75569 [61], 6) correlation of genes upregulated or downregulated by Telmisartan and in calories restricted mice [61]. 7) GSE37643, neuronal ceroid lipofuscinoses (CLN1) [63]. Downregulated genes are noted in blue, upregulated genes are noted in red. (XLSX 423 kb)

Supplemental Table 5

Microarray data of significantly differentially expressed genes between DMSO versus LPS that are used for the IPA (Ingenuity Pathways Analysis). Different IPA outputs are presented in different spreadsheets: 1) lists of genes upregulated or downregulated by LPS, 2) Canonical pathways, 3) Upstream regulators, 4) Diseases and Functions, 5) Networks. (XLSX 241 kb)

Supplemental Table 6

Microarray data of significantly differentially expressed genes between LPS versus LPS + Telmisartan that are used for the IPA (Ingenuity Pathways Analysis). Different IPA outputs are presented in different spreadsheets: 1) lists of genes upregulated or downregulated including statistical significance, fold change and direction, 2) Canonical pathways, 3) Diseases and functions, 4) Upstream regulator, 5) Networks. (XLSX 159 kb)

Supplemental Table 7

Microarray data of significantly differentially expressed genes between LPS + Telmisartan versus LPS + Telmisartan + GW9662 that are used for the IPA (Ingenuity Pathways Analysis). Different IPA outputs are presented in different spreadsheets. 1) List of genes upregulated or downregulated, including statistical significance, fold change and direction. 2) Canonic pathways. 3) Disease and Function. 4) Network. 5) Upstream regulators. (XLSX 101 kb)

Supplemental Table 8

GSEA complete results summary of the gene sets described in Fig. 5. Data represent, in order: 1) GSEA results summary of cultured astrocytes activated with FGF2 and then treated with MKK non-competitive inhibitor U0126 as reported in GSE6675 [114]. 2) GSEA results summary of neuroblastoma cell line SH-SY5Y treated with PDGF and pretreated with the ERK inhibitors U0126 and PD98059 (GSE7403, [117, 144]. 3). GSEA results summary of MCF-7 cell lines. 3a) GSEA results summary of MCF-7 cell lines stably overexpressing a constitutively active EGFR. 3b) GSEA results summary of MCF-7 cell lines stably overexpressing a constitutively active MEK (MAP2K1) [148]. 3c) GSEA results summary of MCF-7 cell lines stably overexpressing a constitutively active Raf1 (GSE3542, [148]. 4) GSEA results summary of GSE49329 murine microglia IL4 up by 2 folds [146]. 5) GSEA results summary of GSE67036 rat CGC upregulated by glutamate and downregulated by candesartan [14]. 6) GSE93695 rat striatum lid+PD98059 + down vs lid (GSE93695 [147]. (XLSX 1055 kb)

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Elkahloun, A.G., Rodriguez, Y., Alaiyed, S. et al. Telmisartan Protects a Microglia Cell Line from LPS Injury Beyond AT1 Receptor Blockade or PPARγ Activation. Mol Neurobiol 56, 3193–3210 (2019). https://doi.org/10.1007/s12035-018-1300-9

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