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The Mycobacterial Adjuvant Analogue TDB Attenuates Neuroinflammation via Mincle-Independent PLC-γ1/PKC/ERK Signaling and Microglial Polarization

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Abstract

Microglial activation has long been recognized as a hallmark of neuroinflammation. Recently, the bacillus Calmette-Guerin (BCG) vaccine has been reported to exert neuroprotective effects against several neurodegenerative disorders. Trehalose-6,6′-dibehenate (TDB) is a synthetic analogue of trehalose-6,6′-dimycolate (TDM, also known as the mycobacterial cord factor) and is a new adjuvant of tuberculosis subunit vaccine currently in clinical trials. Both TDM and TDB can activate macrophages and dendritic cells through binding to C-type lectin receptor Mincle; however, its action mechanism in microglia and their relationship with neuroinflammation are still unknown. In this article, we found that TDB inhibited LPS-induced M1 microglial polarization in primary microglia and BV-2 cells. However, TDB itself had no effects on IKK, p38, and JNK activities or cytokine expression. In contrast, TDB activated ERK1/2 through PLC-γ1/PKC signaling and in turn decreased LPS-induced NF-κB nuclear translocation. Furthermore, TDB-induced AMPK activation via PLC-γ1/calcium/CaMKKβ-dependent pathway and thereby enhanced M2 gene expressions. Interestingly, knocking out Mincle did not alter the anti-inflammatory and M2 polarization effects of TDB in microglia. Conditional media from LPS-stimulated microglial cells can induce in vitro neurotoxicity, and this action was attenuated by TDB. Using a mouse neuroinflammation model, we found that TDB suppressed LPS-induced M1 microglial activation and sickness behavior, but promoted M2 microglial polarization in both WT and Mincle−/− mice. Taken together, our results suggest that TDB can act independently of Mincle to inhibit LPS-induced inflammatory response through PLC-γ1/PKC/ERK signaling and promote microglial polarization towards M2 phenotype via PLC-γ1/calcium/CaMKKβ/AMPK pathway. Thus, TDB may be a promising therapeutic agent for the treatment of neuroinflammatory diseases.

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References

  1. Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15(5):300–312. https://doi.org/10.1038/nrn3722

    Article  CAS  PubMed  Google Scholar 

  2. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140(6):918–934. https://doi.org/10.1016/j.cell.2010.02.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Casano AM, Peri F (2015) Microglia: multitasking specialists of the brain. Dev Cell 32(4):469–477. https://doi.org/10.1016/j.devcel.2015.01.018

    Article  CAS  PubMed  Google Scholar 

  4. Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11(11):775–787. https://doi.org/10.1038/nri3086

    Article  CAS  PubMed  Google Scholar 

  5. Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J (2015) Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol 11(1):56–64. https://doi.org/10.1038/nrneurol.2014.207

    Article  PubMed  Google Scholar 

  6. Xu L, He D, Bai Y (2016) Microglia-mediated inflammation and neurodegenerative disease. Mol Neurobiol 53(10):6709–6715. https://doi.org/10.1007/s12035-015-9593-4

    Article  CAS  PubMed  Google Scholar 

  7. Centers for Disease C, Prevention (2012) Global routine vaccination coverage, 2011. MMWR Morb Mortal Wkly Rep 61(43):883–885

    Google Scholar 

  8. Rodrigues LC, Diwan VK, Wheeler JG (1993) Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis. Int J Epidemiol 22(6):1154–1158

    Article  CAS  PubMed  Google Scholar 

  9. Brenner SR (2014) Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS. Neurology 83(4):380–381. https://doi.org/10.1212/01.wnl.0000452678.33365.c7

    Article  PubMed  Google Scholar 

  10. Lacan G, Dang H, Middleton B, Horwitz MA, Tian J, Melega WP, Kaufman DL (2013) Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. J Neurosci Res 91(10):1292–1302. https://doi.org/10.1002/jnr.23253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zuo Z, Qi F, Yang J, Wang X, Wu Y, Wen Y, Yuan Q, Zou J et al (2017) Immunization with Bacillus Calmette-Guerin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain. Neurobiol Dis 101:27–39. https://doi.org/10.1016/j.nbd.2017.02.001

    Article  CAS  PubMed  Google Scholar 

  12. Lee J, Reinke EK, Zozulya AL, Sandor M, Fabry Z (2008) Mycobacterium bovis bacille Calmette-Guerin infection in the CNS suppresses experimental autoimmune encephalomyelitis and Th17 responses in an IFN-gamma-independent manner. J Immunol 181(9):6201–6212

    Article  CAS  PubMed  Google Scholar 

  13. Yang J, Qi F, Gu H, Zou J, Yang Y, Yuan Q, Yao Z (2016) Neonatal BCG vaccination of mice improves neurogenesis and behavior in early life. Brain Res Bull 120:25–33. https://doi.org/10.1016/j.brainresbull.2015.10.012

    Article  CAS  PubMed  Google Scholar 

  14. Li Q, Zhang Y, Zou J, Qi F, Yang J, Yuan Q, Yao Z (2016) Neonatal vaccination with bacille Calmette-Guerin promotes the dendritic development of hippocampal neurons. Hum Vaccin Immunother 12(1):140–149. https://doi.org/10.1080/21645515.2015.1056954

    Article  PubMed  Google Scholar 

  15. Yang J, Qi F, Yao Z (2016) Neonatal Bacillus Calmette-Guerin vaccination alleviates lipopolysaccharide-induced neurobehavioral impairments and neuroinflammation in adult mice. Mol Med Rep 14(2):1574–1586. https://doi.org/10.3892/mmr.2016.5425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Geisel RE, Sakamoto K, Russell DG, Rhoades ER (2005) In vivo activity of released cell wall lipids of Mycobacterium bovis bacillus Calmette-Guerin is due principally to trehalose mycolates. J Immunol 174(8):5007–5015

    Article  CAS  PubMed  Google Scholar 

  17. Fujita Y, Naka T, McNeil MR, Yano I (2005) Intact molecular characterization of cord factor (trehalose 6,6′-dimycolate) from nine species of mycobacteria by MALDI-TOF mass spectrometry. Microbiology 151(Pt 10):3403–3416. https://doi.org/10.1099/mic.0.28158-0

    Article  CAS  PubMed  Google Scholar 

  18. Hunter RL, Olsen MR, Jagannath C, Actor JK (2006) Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease. Ann Clin Lab Sci 36(4):371–386

    CAS  PubMed  Google Scholar 

  19. van Dissel JT, Joosten SA, Hoff ST, Soonawala D, Prins C, Hokey DA, O'Dee DM, Graves A et al (2014) A novel liposomal adjuvant system, CAF01, promotes long-lived Mycobacterium tuberculosis-specific T-cell responses in human. Vaccine 32(52):7098–7107. https://doi.org/10.1016/j.vaccine.2014.10.036

    Article  CAS  PubMed  Google Scholar 

  20. Roman VR, Jensen KJ, Jensen SS, Leo-Hansen C, Jespersen S, da Silva Te D, Rodrigues CM, Janitzek CM et al (2013) Therapeutic vaccination using cationic liposome-adjuvanted HIV type 1 peptides representing HLA-supertype-restricted subdominant T cell epitopes: safety, immunogenicity, and feasibility in Guinea-Bissau. AIDS Res Hum Retrovir 29(11):1504–1512. https://doi.org/10.1089/AID.2013.0076

    Article  CAS  PubMed  Google Scholar 

  21. Ishikawa E, Ishikawa T, Morita YS, Toyonaga K, Yamada H, Takeuchi O, Kinoshita T, Akira S et al (2009) Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J Exp Med 206(13):2879–2888. https://doi.org/10.1084/jem.20091750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Strasser D, Neumann K, Bergmann H, Marakalala MJ, Guler R, Rojowska A, Hopfner KP, Brombacher F et al (2012) Syk kinase-coupled C-type lectin receptors engage protein kinase C-sigma to elicit Card9 adaptor-mediated innate immunity. Immunity 36(1):32–42. https://doi.org/10.1016/j.immuni.2011.11.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Werninghaus K, Babiak A, Gross O, Holscher C, Dietrich H, Agger EM, Mages J, Mocsai A et al (2009) Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ-Syk-Card9-dependent innate immune activation. J Exp Med 206(1):89–97. https://doi.org/10.1084/jem.20081445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Suzuki Y, Nakano Y, Mishiro K, Takagi T, Tsuruma K, Nakamura M, Yoshimura S, Shimazawa M et al (2013) Involvement of Mincle and Syk in the changes to innate immunity after ischemic stroke. Sci Rep 3:3177. https://doi.org/10.1038/srep03177

    Article  PubMed  PubMed Central  Google Scholar 

  25. He Y, Xu L, Li B, Guo ZN, Hu Q, Guo Z, Tang J, Chen Y et al (2015) Macrophage-inducible C-type lectin/spleen tyrosine kinase signaling pathway contributes to neuroinflammation after subarachnoid hemorrhage in rats. Stroke 46(8):2277–2286. https://doi.org/10.1161/STROKEAHA.115.010088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. de Rivero Vaccari JC, Brand FJ 3rd, Berti AF, Alonso OF, Bullock MR, de Rivero Vaccari JP (2015) Mincle signaling in the innate immune response after traumatic brain injury. J Neurotrauma 32(4):228–236. https://doi.org/10.1089/neu.2014.3436

    Article  PubMed  Google Scholar 

  27. Xie Y, Guo H, Wang L, Xu L, Zhang X, Yu L, Liu Q, Li Y et al (2017) Human albumin attenuates excessive innate immunity via inhibition of microglial Mincle/Syk signaling in subarachnoid hemorrhage. Brain Behav Immun 60:346–360. https://doi.org/10.1016/j.bbi.2016.11.004

    Article  CAS  PubMed  Google Scholar 

  28. Lee WB, Kang JS, Choi WY, Zhang Q, Kim CH, Choi UY, Kim-Ha J, Kim YJ (2016) Mincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution. Nat Commun 7:11322. https://doi.org/10.1038/ncomms11322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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 

  30. Lee CJ, Lee SS, Chen SC, Ho FM, Lin WW (2005) Oregonin inhibits lipopolysaccharide-induced iNOS gene transcription and upregulates HO-1 expression in macrophages and microglia. Br J Pharmacol 146(3):378–388. https://doi.org/10.1038/sj.bjp.0706336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Saura J, Tusell JM, Serratosa J (2003) High-yield isolation of murine microglia by mild trypsinization. Glia 44(3):183–189. https://doi.org/10.1002/glia.10274

    Article  PubMed  Google Scholar 

  32. Jo M, Kim JH, Song GJ, Seo M, Hwang EM, Suk K (2017) Astrocytic orosomucoid-2 modulates microglial activation and neuroinflammation. J Neurosci 37(11):2878–2894. https://doi.org/10.1523/JNEUROSCI.2534-16.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lin YC, Huang DY, Chu CL, Lin YL, Lin WW (2013) The tyrosine kinase Syk differentially regulates Toll-like receptor signaling downstream of the adaptor molecules TRAF6 and TRAF3. Sci Signal 6(289):ra71. https://doi.org/10.1126/scisignal.2003973

    Article  CAS  PubMed  Google Scholar 

  34. Lin YC, Huang DY, Wang JS, Lin YL, Hsieh SL, Huang KC, Lin WW (2015) Syk is involved in NLRP3 inflammasome-mediated caspase-1 activation through adaptor ASC phosphorylation and enhanced oligomerization. J Leukoc Biol. doi:https://doi.org/10.1189/jlb.3HI0814-371RR

    Article  CAS  PubMed  Google Scholar 

  35. Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173(4):649–665. https://doi.org/10.1111/bph.13139

    Article  CAS  PubMed  Google Scholar 

  36. Sekar P, Huang DY, Chang SF, Lin WW (2018) Coordinate effects of P2X7 and extracellular acidification in microglial cells. Oncotarget 9 (16):12718–12731. doi:https://doi.org/10.18632/oncotarget.24331, 12718, 12731

  37. Agger EM, Rosenkrands I, Hansen J, Brahimi K, Vandahl BS, Aagaard C, Werninghaus K, Kirschning C et al (2008) Cationic liposomes formulated with synthetic mycobacterial cordfactor (CAF01): a versatile adjuvant for vaccines with different immunological requirements. PLoS One 3(9):e3116. https://doi.org/10.1371/journal.pone.0003116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Milicic A, Kaur R, Reyes-Sandoval A, Tang CK, Honeycutt J, Perrie Y, Hill AV (2012) Small cationic DDA:TDB liposomes as protein vaccine adjuvants obviate the need for TLR agonists in inducing cellular and humoral responses. PLoS One 7(3):e34255. https://doi.org/10.1371/journal.pone.0034255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 5:15. https://doi.org/10.1186/1742-2094-5-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC (2011) CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147(4):868–880. https://doi.org/10.1016/j.cell.2011.09.051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lu R, Pan H, Shively JE (2012) CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex. PLoS Pathog 8(4):e1002597. https://doi.org/10.1371/journal.ppat.1002597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Honjoh C, Chihara K, Yoshiki H, Yamauchi S, Takeuchi K, Kato Y, Hida Y, Ishizuka T et al (2017) Association of C-type lectin Mincle with FcƐRIβγ subunits leads to functional activation of RBL-2H3 cells through Syk. Sci Rep 7:46064. https://doi.org/10.1038/srep46064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Grahame Hardie D (2014) AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease. J Intern Med 276(6):543–559. https://doi.org/10.1111/joim.12268

    Article  CAS  PubMed  Google Scholar 

  44. Racioppi L, Noeldner PK, Lin F, Arvai S, Means AR (2012) Calcium/calmodulin-dependent protein kinase kinase 2 regulates macrophage-mediated inflammatory responses. J Biol Chem 287(14):11579–11591. https://doi.org/10.1074/jbc.M111.336032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Du L, Zhang Y, Chen Y, Zhu J, Yang Y, Zhang HL (2016) Role of microglia in neurological disorders and their potentials as a therapeutic target. Mol Neurobiol 54:7567–7584. https://doi.org/10.1007/s12035-016-0245-0

    Article  CAS  PubMed  Google Scholar 

  46. Schoenen H, Huber A, Sonda N, Zimmermann S, Jantsch J, Lepenies B, Bronte V, Lang R (2014) Differential control of Mincle-dependent cord factor recognition and macrophage responses by the transcription factors C/EBPβ and HIF1α. J Immunol 193(7):3664–3675. https://doi.org/10.4049/jimmunol.1301593

    Article  CAS  PubMed  Google Scholar 

  47. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69. https://doi.org/10.1038/nrn2038

    Article  CAS  PubMed  Google Scholar 

  48. Greco SH, Mahmood SK, Vahle AK, Ochi A, Batel J, Deutsch M, Barilla R, Seifert L et al (2016) Mincle suppresses Toll-like receptor 4 activation. J Leukoc Biol 100(1):185–194. https://doi.org/10.1189/jlb.3A0515-185R

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Arumugam TV, Manzanero S, Furtado M, Biggins PJ, Hsieh YH, Gelderblom M, MacDonald KP, Salimova E et al (2017) An atypical role for the myeloid receptor Mincle in central nervous system injury. J Cereb Blood Flow Metab 37(6):2098–2111. https://doi.org/10.1177/0271678X16661201

    Article  CAS  PubMed  Google Scholar 

  50. Lv LL, Tang PM, Li CJ, You YK, Li J, Huang XR, Ni J, Feng M et al (2017) The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation. Kidney Int 91(3):587–602. https://doi.org/10.1016/j.kint.2016.10.020

    Article  CAS  PubMed  Google Scholar 

  51. Zhao XQ, Zhu LL, Chang Q, Jiang C, You Y, Luo T, Jia XM, Lin X (2014) C-type lectin receptor dectin-3 mediates trehalose 6,6′-dimycolate (TDM)-induced Mincle expression through CARD9/Bcl10/MALT1-dependent nuclear factor (NF)-κB activation. J Biol Chem 289(43):30052–30062. https://doi.org/10.1074/jbc.M114.588574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dambuza IM, Brown GD (2015) C-type lectins in immunity: recent developments. Curr Opin Immunol 32:21–27. https://doi.org/10.1016/j.coi.2014.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mocsai A, Ruland J, Tybulewicz VL (2010) The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 10(6):387–402. https://doi.org/10.1038/nri2765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zong Y, Ai QL, Zhong LM, Dai JN, Yang P, He Y, Sun J, Ling EA et al (2012) Ginsenoside Rg1 attenuates lipopolysaccharide-induced inflammatory responses via the phospholipase C-gamma1 signaling pathway in murine BV-2 microglial cells. Curr Med Chem 19(5):770–779

    Article  CAS  PubMed  Google Scholar 

  55. Yang WS, Jeong D, Yi YS, Lee BH, Kim TW, Htwe KM, Kim YD, Yoon KD et al (2014) Myrsine seguinii ethanolic extract and its active component quercetin inhibit macrophage activation and peritonitis induced by LPS by targeting to Syk/Src/IRAK-1. J Ethnopharmacol 151(3):1165–1174. https://doi.org/10.1016/j.jep.2013.12.033

    Article  CAS  PubMed  Google Scholar 

  56. Yin H, Zhou H, Kang Y, Zhang X, Duan X, Alnabhan R, Liang S, Scott DA et al (2016) Syk negatively regulates TLR4-mediated IFNβ and IL-10 production and promotes inflammatory responses in dendritic cells. Biochim Biophys Acta 1860(3):588–598. https://doi.org/10.1016/j.bbagen.2015.12.012

    Article  CAS  PubMed  Google Scholar 

  57. Han C, Jin J, Xu S, Liu H, Li N, Cao X (2010) Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat Immunol 11(8):734–742. https://doi.org/10.1038/ni.1908

    Article  CAS  PubMed  Google Scholar 

  58. Hou CH, Lin J, Huang SC, Hou SM, Tang CH (2009) Ultrasound stimulates NF-kappaB activation and iNOS expression via the Ras/Raf/MEK/ERK signaling pathway in cultured preosteoblasts. J Cell Physiol 220(1):196–203. https://doi.org/10.1002/jcp.21751

    Article  CAS  PubMed  Google Scholar 

  59. Lin CC, Shih CH, Yang YL, Bien MY, Lin CH, Yu MC, Sureshbabu M, Chen BC (2011) Thrombin induces inducible nitric oxide synthase expression via the MAPK, MSK1, and NF-κB signaling pathways in alveolar macrophages. Eur J Pharmacol 672(1–3):180–187. https://doi.org/10.1016/j.ejphar.2011.10.005

    Article  CAS  PubMed  Google Scholar 

  60. Carter AB, Hunninghake GW (2000) A constitutive active MEK → ERK pathway negatively regulates NF-κB-dependent gene expression by modulating TATA-binding protein phosphorylation. J Biol Chem 275(36):27858–27864. https://doi.org/10.1074/jbc.M003599200

    Article  CAS  PubMed  Google Scholar 

  61. Maeng YS, Min JK, Kim JH, Yamagishi A, Mochizuki N, Kwon JY, Park YW, Kim YM et al (2006) ERK is an anti-inflammatory signal that suppresses expression of NF-κB-dependent inflammatory genes by inhibiting IKK activity in endothelial cells. Cell Signal 18(7):994–1005. https://doi.org/10.1016/j.cellsig.2005.08.007

    Article  CAS  PubMed  Google Scholar 

  62. Ahmed KM, Dong S, Fan M, Li JJ (2006) Nuclear factor-kappaB p65 inhibits mitogen-activated protein kinase signaling pathway in radioresistant breast cancer cells. Mol Cancer Res 4(12):945–955. https://doi.org/10.1158/1541-7786.MCR-06-0291

    Article  CAS  PubMed  Google Scholar 

  63. Oyesanya RA, Lee ZP, Wu J, Chen J, Song Y, Mukherjee A, Dent P, Kordula T et al (2008) Transcriptional and post-transcriptional mechanisms for lysophosphatidic acid-induced cyclooxygenase-2 expression in ovarian cancer cells. FASEB J 22(8):2639–2651. https://doi.org/10.1096/fj.07-101428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kang YJ, Mbonye UR, DeLong CJ, Wada M, Smith WL (2007) Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. Prog Lipid Res 46(2):108–125. https://doi.org/10.1016/j.plipres.2007.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262. https://doi.org/10.1038/nrm3311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Amato S, Man HY (2011) Bioenergy sensing in the brain: the role of AMP-activated protein kinase in neuronal metabolism, development and neurological diseases. Cell Cycle 10(20):3452–3460. https://doi.org/10.4161/cc.10.20.17953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Li J, McCullough LD (2010) Effects of AMP-activated protein kinase in cerebral ischemia. J Cereb Blood Flow Metab 30(3):480–492. https://doi.org/10.1038/jcbfm.2009.255

    Article  CAS  PubMed  Google Scholar 

  68. Giri S, Nath N, Smith B, Viollet B, Singh AK, Singh I (2004) 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. J Neurosci 24(2):479–487. https://doi.org/10.1523/JNEUROSCI.4288-03.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nath N, Khan M, Paintlia MK, Singh I, Hoda MN, Giri S (2009) Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol 182(12):8005–8014. https://doi.org/10.4049/jimmunol.0803563

    Article  CAS  PubMed  Google Scholar 

  70. Mounier R, Theret M, Arnold L, Cuvellier S, Bultot L, Goransson O, Sanz N, Ferry A et al (2013) AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell Metab 18(2):251–264. https://doi.org/10.1016/j.cmet.2013.06.017

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Shie-Liang Hsieh (Genomics Research Center, Academia Sinica, Taipei, Taiwan) for Mincle−/− mice and Dr. Wen-Mei Fu (Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan) for providing SH-SY5Y cells.

Funding

This study was financially supported by the Ministry of Science and Technology, Taiwan (MOST 103-2320-B-002-069-MY3; 106-2321-B-002-021) and National Taiwan University Hospital (UN107-032).

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Authors and Affiliations

  1. Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan

    Mahendravarman Mohanraj, Ponarulselvam Sekar, Shwu-Fen Chang & Wan-Wan Lin

  2. Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Horng-Huei Liou & Wan-Wan Lin

  3. Department of Neurology, National Taiwan University, Taipei, Taiwan

    Horng-Huei Liou

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  1. Mahendravarman Mohanraj
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  2. Ponarulselvam Sekar
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  3. Horng-Huei Liou
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  5. Wan-Wan Lin
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Corresponding author

Correspondence to Wan-Wan Lin.

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The study was approved by the National Taiwan University College of Medicine Ethics Committee in accordance with their guidelines for the care of animals (protocol no. 20110047).

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The authors declare that they have no competing interests.

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Supplementary Figure 1

Activation of PKC/ERK and CaMKKβ/AMPK signaling pathways are independent of each other. BV-2 cells were treated with vehicle control or pre-treated with U0126 (10 μM) (A), GF1090203X (5 μM) (B), or STO-609 (10 μM) (C) for 30 min, then treated with TDB (50 μg/ml), LPS (100 ng/ml) (A-D) and/or A769662 (20 μM) (D) for different time periods as indicated. Total cell lysates were subjected to SDS-PAGE followed by immunoblotting analysis. Results were representative from 3 independent experiments. (GIF 234 kb)

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Supplementary Figure 2

TDB induced inflammatory responses in BMDMs but not in BV-2 microglia. BV-2 microglial cells (A) or BMDMs (B) were treated with vehicle or TDB (50 μg/ml) that was either in suspension or plate-bound form for 48 h. Isopropyl alcohol is the vehicle for coated plates, while 0.01% DMSO is the vehicle for TDB treatment in suspension manner. Total mRNA was extracted and reversely transcribed for quantitative PCR analysis of COX-2, iNOS, TNF-α, proIL-1β, IL-6, Mincle, IFN-β and MIP2 mRNA. Values were normalized to β-actin gene expression and are expressed relative to the control group. Data were presented as mean ± SEM from 3 independent experiments. *p < 0.05, indicating the significant increase in response to TDB. (GIF 117 kb)

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Mohanraj, M., Sekar, P., Liou, HH. et al. The Mycobacterial Adjuvant Analogue TDB Attenuates Neuroinflammation via Mincle-Independent PLC-γ1/PKC/ERK Signaling and Microglial Polarization. Mol Neurobiol 56, 1167–1187 (2019). https://doi.org/10.1007/s12035-018-1135-4

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  • DOI: https://doi.org/10.1007/s12035-018-1135-4

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