1887

Journal of General Virology header logo

Volume 104, Issue 5

IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia Open Access

Abstract

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are a common source of morbidity in people living with HIV (PLWH). Although antiretroviral therapy (ART) has lessened the severity of neurocognitive disorders, cognitive impairment still occurs in PLWH receiving ART. The pathogenesis of HAND is likely multifaceted, but common factors include the persistence of HIV transcription within the central nervous system, higher levels of pro-inflammatory cytokines in the cerebrospinal fluid, and the presence of activated microglia. Toll-like receptor (TLR) 7 and TLR8 are innate pathogen recognition receptors located in microglia and other immune and non-immune cells that can recognise HIV RNA and trigger pro-inflammatory responses. IL-1 receptor-associated kinase (IRAK) 1 is key to these signalling pathways. Here, we show that IRAK1 inhibition inhibits the TLR7 and TLR8-dependent pro-inflammatory response to HIV RNA. Using genetic and pharmacological inhibition, we demonstrate that inhibition of IRAK1 prevents IRAK1 phosphorylation and ubiquitination, and the subsequent recruitment of TRAF6 and the TAK1 complex to IRAK1, resulting in the inhibition of downstream signalling and the suppression of pro-inflammatory cytokine and chemokine release.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): HIV , IRAK1 , microglia , pacritinib , TLR7 and TLR8
Funding
This study was supported by the:
  • International Maternal Pediatric Adolescent AIDS Clinical Trials Network
    • Principle Award Recipient: StephenA. Spector
  • National Institute of Neurological Disorders and Stroke (Award R01NS104015)
    • Principle Award Recipient: StephenA. Spector
  • University of South Dakota
    • Principle Award Recipient: GrantR Campbell
  • National Institute of Mental Health (Award R01MH128021)
    • Principle Award Recipient: GrantR Campbell
© 2023 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001858
2023-05-31
2024-04-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/104/5/jgv001858.html?itemId=/content/journal/jgv/10.1099/jgv.0.001858&mimeType=html&fmt=ahah

References

  1. Heaton RK, Clifford DB, Franklin DR, Woods SP, Ake C et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 2010; 75:2087–2096 [View Article] [PubMed]
     [Google Scholar]
  2. Wang Y, Liu M, Lu Q, Farrell M, Lappin JM et al. Global prevalence and burden of HIV-associated neurocognitive disorder: a meta-analysis. Neurology 2020; 95:e2610–e2621 [View Article] [PubMed]
     [Google Scholar]
  3. Strain MC, Letendre S, Pillai SK, Russell T, Ignacio CC. Genetic composition of human immunodeficiency virus type 1 in cerebrospinal fluid and blood without treatment and during failing antiretroviral therapy. J Virol 2005; 79:1772–1788 [View Article]
     [Google Scholar]
  4. Gama L, Abreu CM, Shirk EN, Price SL, Li M. Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques. AIDS 2017; 31:5–14 [View Article] [PubMed]
     [Google Scholar]
  5. Suzuki K, Zaunders J, Gates TM, Levert A, Butterly S et al. Elevation of cell-associated HIV-1 transcripts in CSF CD4+ T cells, despite effective antiretroviral therapy, is linked to brain injury. Proc Natl Acad Sci 2022; 119:48 [View Article] [PubMed]
     [Google Scholar]
  6. Montoya JL, Campbell LM, Paolillo EW, Ellis RJ, Letendre SL. Inflammation relates to poorer complex motor performance among adults living with HIV on suppressive antiretroviral therapy. J Acquir Immune Defic Syndr 2019; 80:15–23 [View Article] [PubMed]
     [Google Scholar]
  7. Bsibsi M, Ravid R, Gveric D, van Noort JM. Broad expression of toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 2002; 61:1013–1021 [View Article] [PubMed]
     [Google Scholar]
  8. Trillo-Pazos G, Diamanturos A, Rislove L, Menza T, Chao W et al. Detection of HIV-1 DNA in microglia/ macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection. Brain Pathol 2003; 13:144–154 [View Article] [PubMed]
     [Google Scholar]
  9. Thompson KA, Cherry CL, Bell JE, McLean CA. Brain cell reservoirs of latent virus in presymptomatic HIV-infected individuals. Am J Pathol 2011; 179:1623–1629 [View Article] [PubMed]
     [Google Scholar]
  10. Avalos CR, Abreu CM, Queen SE, Li M, Price S et al. Brain macrophages in simian immunodeficiency virus-infected, antiretroviral-suppressed macaques: a functional latent reservoir. mBio 2017; 8:e01186-17 [View Article] [PubMed]
     [Google Scholar]
  11. Ko A, Kang G, Hattler JB, Galadima HI, Zhang J et al. Macrophages but not astrocytes harbor HIV DNA in the brains of HIV-1-infected aviremic individuals on suppressive antiretroviral therapy. J Neuroimmune Pharmacol 2019; 14:110–119 [View Article] [PubMed]
     [Google Scholar]
  12. Donoso M, D’Amico D, Valdebenito S, Hernandez CA, Prideaux B et al. Identification, quantification, and characterization of HIV-1 reservoirs in the human brain. Cells 2022; 11:2379 [View Article] [PubMed]
     [Google Scholar]
  13. Plaza-Jennings AL, Valada A, O’Shea C, Iskhakova M, Hu B et al. HIV integration in the human brain is linked to microglial activation and 3D genome remodeling. Mol Cell 2022; 82:4647–4663 [View Article] [PubMed]
     [Google Scholar]
  14. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004; 303:1526–1529 [View Article] [PubMed]
     [Google Scholar]
  15. Greulich W, Wagner M, Gaidt MM, Stafford C, Cheng Y et al. TLR8 is a sensor of RNase T2 degradation products. Cell 2019; 179:1264–1275 [View Article] [PubMed]
     [Google Scholar]
  16. Campbell GR, To RK, Hanna J, Spector SA. SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the NLRP3 inflammasome in human macrophages through a non-classical pathway. iScience 2021; 24:102295 [View Article] [PubMed]
     [Google Scholar]
  17. Salvi V, Nguyen HO, Sozio F, Schioppa T, Gaudenzi C et al. SARS-CoV-2-associated ssRNAs activate inflammation and immunity via TLR7/8. JCI Insight 2021; 6:e150542 [View Article] [PubMed]
     [Google Scholar]
  18. Liu K, Sato R, Shibata T, Hiranuma R, Reuter T et al. Skewed endosomal RNA responses from TLR7 to TLR3 in RNase T2-deficient macrophages. Int Immunol 2021; 33:479–490 [View Article] [PubMed]
     [Google Scholar]
  19. Brikos C, Wait R, Begum S, O’Neill LAJ, Saklatvala J. Mass spectrometric analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and IRAK-4 as the stable components. Mol Cell Proteomics 2007; 6:1551–1559 [View Article] [PubMed]
     [Google Scholar]
  20. Lin SC, Lo YC, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 2010; 465:885–890 [View Article] [PubMed]
     [Google Scholar]
  21. Cushing L, Stochaj W, Siegel M, Czerwinski R, Dower K et al. Interleukin 1/Toll-like receptor-induced autophosphorylation activates interleukin 1 receptor-associated kinase 4 and controls cytokine induction in a cell type-specific manner. J Biol Chem 2014; 289:10865–10875 [View Article] [PubMed]
     [Google Scholar]
  22. Ferrao R, Zhou H, Shan Y, Liu Q, Li Q et al. IRAK4 dimerization and trans-autophosphorylation are induced by myddosome assembly. Mol Cell 2014; 55:891–903 [View Article] [PubMed]
     [Google Scholar]
  23. Vollmer S, Strickson S, Zhang T, Gray N, Lee KL et al. The mechanism of activation of IRAK1 and IRAK4 by interleukin-1 and toll-like receptor agonists. Biochem J 2017; 474:2027–2038 [View Article] [PubMed]
     [Google Scholar]
  24. Jiang Z, Johnson HJ, Nie H, Qin J, Bird TA et al. Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex. J Biol Chem 2003; 278:10952–10956 [View Article] [PubMed]
     [Google Scholar]
  25. Cui W, Xiao N, Xiao H, Zhou H, Yu M et al. β-TrCP-mediated IRAK1 degradation releases TAK1-TRAF6 from the membrane to the cytosol for TAK1-dependent NF-κB activation. Mol Cell Biol 2012; 32:3990–4000 [View Article] [PubMed]
     [Google Scholar]
  26. Emmerich CH, Ordureau A, Strickson S, Arthur JSC, Pedrioli PGA et al. Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. Proc Natl Acad Sci 2013; 110:15247–15252 [View Article] [PubMed]
     [Google Scholar]
  27. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124:783–801 [View Article] [PubMed]
     [Google Scholar]
  28. Ghosh TK, Mickelson DJ, Fink J, Solberg JC, Inglefield JR et al. Toll-like receptor (TLR) 2-9 agonists-induced cytokines and chemokines: I. Comparison with T cell receptor-induced responses. Cell Immunol 2006; 243:48–57 [View Article] [PubMed]
     [Google Scholar]
  29. Vierbuchen T, Bang C, Rosigkeit H, Schmitz RA, Heine H. The human-associated archaeon Methanosphaera stadtmanae is recognized through its RNA and induces TLR8-dependent NLRP3 inflammasome activation. Front Immunol 2017; 8:1535 [View Article] [PubMed]
     [Google Scholar]
  30. Lehmann SM, Rosenberger K, Krüger C, Habbel P, Derkow K et al. Extracellularly delivered single-stranded viral RNA causes neurodegeneration dependent on TLR7. J Immunol 2012; 189:1448–1458 [View Article] [PubMed]
     [Google Scholar]
  31. Rosenberger K, Derkow K, Dembny P, Krüger C, Schott E et al. The impact of single and pairwise Toll-like receptor activation on neuroinflammation and neurodegeneration. J Neuroinflammation 2014; 11:166 [View Article] [PubMed]
     [Google Scholar]
  32. Rawat P, Teodorof-Diedrich C, Spector SA. Human immunodeficiency virus type-1 single-stranded RNA activates the NLRP3 inflammasome and impairs autophagic clearance of damaged mitochondria in human microglia. Glia 2019; 67:802–824 [View Article] [PubMed]
     [Google Scholar]
  33. Wang Z, Wesche H, Stevens T, Walker N, Yeh WC. IRAK-4 inhibitors for inflammation. Curr Top Med Chem 2009; 9:724–737 [View Article] [PubMed]
     [Google Scholar]
  34. Flannery S, Bowie AG. The interleukin-1 receptor-associated kinases: critical regulators of innate immune signalling. Biochem Pharmacol 2010; 80:1981–1991 [View Article] [PubMed]
     [Google Scholar]
  35. Cushing L, Winkler A, Jelinsky SA, Lee K, Korver W et al. IRAK4 kinase activity controls Toll-like receptor-induced inflammation through the transcription factor IRF5 in primary human monocytes. J Biol Chem 2017; 292:18689–18698 [View Article] [PubMed]
     [Google Scholar]
  36. Singer JW, Fleischman A, Al-Fayoumi S, Mascarenhas JO, Yu Q et al. Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy. Oncotarget 2018; 9:33416–33439 [View Article] [PubMed]
     [Google Scholar]
  37. William AD, Lee A-H, Blanchard S, Poulsen A, Teo EL et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem 2011; 54:4638–4658 [View Article] [PubMed]
     [Google Scholar]
  38. Rawat P, Spector SA. Development and characterization of a human microglia cell model of HIV-1 infection. J Neurovirol 2017; 23:33–46 [View Article] [PubMed]
     [Google Scholar]
  39. Ryan KJ, White CC, Patel K, Xu J, Olah M et al. A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants. Sci Transl Med 2017; 9:eaai7635 [View Article] [PubMed]
     [Google Scholar]
  40. Rai MA, Hammonds J, Pujato M, Mayhew C, Roskin K et al. Comparative analysis of human microglial models for studies of HIV replication and pathogenesis. Retrovirology 2020; 17:35 [View Article] [PubMed]
     [Google Scholar]
  41. Rawat P, Brummel SS, Singh KK, Kim J, Frazer KA et al. Genomics links inflammation with neurocognitive impairment in children living with human immunodeficiency virus type-1. J Infect Dis 2021; 224:870–880 [View Article] [PubMed]
     [Google Scholar]
  42. Gartner S, Markovits P, Markovitz DM, Kaplan MH, Gallo RC et al. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 1986; 233:215–219 [View Article] [PubMed]
     [Google Scholar]
  43. Popovic M, Gartner S, Read-Connole E, Beaver B, Reitz M. Cell tropism and expression of HIV-1 isolates in natural targets. In Girard M, Valette L. eds Retroviruses of Human AIDS and Related Animal Diseases, Colloque Des Cent Gardes Marnes-La-Coquette: Pasteur Vaccins; 1989 pp 21–27
     [Google Scholar]
  44. Campbell GR, Bruckman RS, Chu Y-L, Trout RN, Spector SA. SMAC mimetics induce autophagy-dependent apoptosis of HIV-1-infected resting memory CD4+ T cells. Cell Host Microbe 2018; 24:689–702 [View Article] [PubMed]
     [Google Scholar]
  45. Barrat FJ, Meeker T, Gregorio J, Chan JH, Uematsu S et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 2005; 202:1131–1139 [View Article] [PubMed]
     [Google Scholar]
  46. Campbell GR, To RK, Zhang G, Spector SA. SMAC mimetics induce autophagy-dependent apoptosis of HIV-1-infected macrophages. Cell Death Dis 2020; 11:590 [View Article] [PubMed]
     [Google Scholar]
  47. Campbell GR, Rawat P, Spector SA. Pacritinib inhibition of IRAK1 blocks aberrant TLR8 signalling by SARS-CoV-2 and HIV-1-derived RNA. J Innate Immun 2022; 15:96–106 [View Article] [PubMed]
     [Google Scholar]
  48. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 2012; 9:676–682 [View Article] [PubMed]
     [Google Scholar]
  49. Bergemann TL, Wilson J. Proportion statistics to detect differentially expressed genes: a comparison with log-ratio statistics. BMC Bioinformatics 2011; 12:228 [View Article] [PubMed]
     [Google Scholar]
  50. Schlaepfer E, Audigé A, Joller H, Speck RF. TLR7/8 triggering exerts opposing effects in acute versus latent HIV infection. J Immunol 2006; 176:2888–2895 [View Article] [PubMed]
     [Google Scholar]
  51. Campbell GR, Rawat P, Bruckman RS, Spector SA. Human immunodeficiency virus type 1 Nef inhibits autophagy through transcription factor EB sequestration. PLoS Pathog 2015; 11:e1005018 [View Article] [PubMed]
     [Google Scholar]
  52. Meås HZ, Haug M, Beckwith MS, Louet C, Ryan L et al. Sensing of HIV-1 by TLR8 activates human T cells and reverses latency. Nat Commun 2020; 11:147 [View Article] [PubMed]
     [Google Scholar]
  53. Campbell GR, Spector SA. Toll-like receptor 8 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1. PLoS Pathog 2012; 8:e1003017 [View Article] [PubMed]
     [Google Scholar]
  54. Ben Haij N, Leghmari K, Planès R, Thieblemont N, Bahraoui E. HIV-1 Tat protein binds to TLR4-MD2 and signals to induce TNF-α and IL-10. Retrovirology 2013; 10:123 [View Article] [PubMed]
     [Google Scholar]
  55. Henrick BM, Yao X-D, Rosenthal KL. INFANT study team HIV-1 structural proteins serve as PAMPs for TLR2 heterodimers significantly increasing infection and innate immune activation. Front Immunol 2015; 6:426 [View Article] [PubMed]
     [Google Scholar]
  56. Song H, DeSantis M, Tian C, Cheng W. Dynasore inhibition on productive infection of HIV-1 in commonly used cell lines is independent of transferrin endocytosis. Matters 2018; 2018:201805000001 [View Article] [PubMed]
     [Google Scholar]
  57. Yamin TT, Miller DK. The interleukin-1 receptor-associated kinase is degraded by proteasomes following its phosphorylation. J Biol Chem 1997; 272:21540–21547 [View Article] [PubMed]
     [Google Scholar]
  58. Pauls E, Nanda SK, Smith H, Toth R, Arthur JSC et al. Two phases of inflammatory mediator production defined by the study of IRAK2 and IRAK1 knock-in mice. J Immunol 2013; 191:2717–2730 [View Article] [PubMed]
     [Google Scholar]
  59. Moen SH, Ehrnström B, Kojen JF, Yurchenko M, Beckwith KS et al. Human toll-like receptor 8 (TLR8) is an important sensor of pyogenic bacteria, and is attenuated by cell surface TLR signaling. Front Immunol 2019; 10:1209 [View Article] [PubMed]
     [Google Scholar]
  60. Costa-Junior HM, Sarmento Vieira F, Coutinho-Silva R. C terminus of the P2X7 receptor: treasure hunting. Purinergic Signal 2011; 7:7–19 [View Article] [PubMed]
     [Google Scholar]
  61. Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL et al. Human monocytes engage an alternative inflammasome pathway. Immunity 2016; 44:833–846 [View Article] [PubMed]
     [Google Scholar]
  62. Hatcher JM, Yang G, Wang L, Ficarro SB, Buhrlage S et al. Discovery of a selective, covalent IRAK1 inhibitor with antiproliferative activity in MYD88 mutated B-cell lymphoma. ACS Med Chem Lett 2020; 11:2238–2243 [View Article] [PubMed]
     [Google Scholar]
  63. Lopez-Pelaez M, Lamont DJ, Peggie M, Shpiro N, Gray NS et al. Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells. Proc Natl Acad Sci 2014; 111:17432–17437 [View Article] [PubMed]
     [Google Scholar]
  64. Zhang J, Clark K, Lawrence T, Peggie MW, Cohen P. An unexpected twist to the activation of IKKβ: TAK1 primes IKKβ for activation by autophosphorylation. Biochem J 2014; 461:531–537 [View Article] [PubMed]
     [Google Scholar]
  65. Tenorio AR, Zheng Y, Bosch RJ, Krishnan S, Rodriguez B et al. Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis 2014; 210:1248–1259 [View Article] [PubMed]
     [Google Scholar]
  66. Utay NS, Hunt PW. Role of immune activation in progression to AIDS. Curr Opin HIV AIDS 2016; 11:131–137 [View Article] [PubMed]
     [Google Scholar]
  67. Das Sarma J. Microglia-mediated neuroinflammation is an amplifier of virus-induced neuropathology. J Neurovirol 2014; 20:122–136 [View Article] [PubMed]
     [Google Scholar]
  68. Guo S, Wang H, Yin Y. Microglia polarization from M1 to M2 in neurodegenerative diseases. Front Aging Neurosci 2022; 14:815347 [View Article] [PubMed]
     [Google Scholar]
  69. Zhao ML, Kim MO, Morgello S, Lee SC. Expression of inducible nitric oxide synthase, interleukin-1 and caspase-1 in HIV-1 encephalitis. J Neuroimmunol 2001; 115:182–191 [View Article] [PubMed]
     [Google Scholar]
  70. Yuan L, Qiao L, Wei F, Yin J, Liu L et al. Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China. J Neurovirol 2013; 19:144–149 [View Article] [PubMed]
     [Google Scholar]
  71. Yuan L, Liu A, Qiao L, Sheng B, Xu M et al. The relationship of CSF and plasma cytokine levels in HIV infected patients with neurocognitive impairment. Biomed Res Int 2015; 2015:506872 [View Article] [PubMed]
     [Google Scholar]
  72. Tiraboschi JM, Muñoz-Moreno JA, Puertas MC, Alonso-Villaverde C, Prats A et al. Viral and inflammatory markers in cerebrospinal fluid of patients with HIV-1-associated neurocognitive impairment during antiretroviral treatment switch. HIV Med 2015; 16:388–392 [View Article] [PubMed]
     [Google Scholar]
  73. Bandera A, Taramasso L, Bozzi G, Muscatello A, Robinson JA et al. HIV-associated neurocognitive impairment in the modern ART era: are we close to discovering reliable biomarkers in the setting of virological suppression?. Front Aging Neurosci 2019; 11:187 [View Article] [PubMed]
     [Google Scholar]
  74. Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdörfer B et al. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 2002; 168:4531–4537 [View Article] [PubMed]
     [Google Scholar]
  75. Alexopoulou L, Desnues B, Demaria O. Le récepteur Toll-like 8: un TLR pas comme les autres. Med Sci 2012; 28:96–102 [View Article]
     [Google Scholar]
  76. Tanji H, Ohto U, Shibata T, Taoka M, Yamauchi Y et al. Toll-like receptor 8 senses degradation products of single-stranded RNA. Nat Struct Mol Biol 2015; 22:109–115 [View Article] [PubMed]
     [Google Scholar]
  77. Zhang Z, Ohto U, Shibata T, Krayukhina E, Taoka M et al. Structural analysis reveals that Toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA. Immunity 2016; 45:737–748 [View Article] [PubMed]
     [Google Scholar]
  78. Zhang Z, Ohto U, Shibata T, Taoka M, Yamauchi Y et al. Structural analyses of Toll-like receptor 7 reveal detailed RNA sequence specificity and recognition mechanism of agonistic ligands. Cell Rep 2018; 25:3371–3381 [View Article] [PubMed]
     [Google Scholar]
  79. Hung Y-F, Chen C-Y, Shih Y-C, Liu H-Y, Huang C-M et al. Endosomal TLR3, TLR7, and TLR8 control neuronal morphology through different transcriptional programs. J Cell Biol 2018; 217:2727–2742 [View Article] [PubMed]
     [Google Scholar]
  80. Chen C-Y, Shih Y-C, Hung Y-F, Hsueh Y-P. Beyond defense: regulation of neuronal morphogenesis and brain functions via Toll-like receptors. J Biomed Sci 2019; 26:90 [View Article] [PubMed]
     [Google Scholar]
  81. Seong K-J, Choi S, Lee H-G, Rhee JH, Lee JH et al. Toll-like receptor 5 promotes the neurogenesis from embryonic stem cells and adult hippocampal neural stem cells in mice. Stem Cells 2022; 40:303–317 [View Article] [PubMed]
     [Google Scholar]
  82. Squillace S, Salvemini D. Toll-like receptor-mediated neuroinflammation: relevance for cognitive dysfunctions. Trends Pharmacol Sci 2022; 43:726–739 [View Article] [PubMed]
     [Google Scholar]
  83. Paudel YN, Angelopoulou E, Piperi C, Othman I, Aamir K et al. Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): from risk factors to therapeutic targeting. Cells 2020; 9:383 [View Article] [PubMed]
     [Google Scholar]
  84. Li H, Liu S, Han J, Li S, Gao X et al. Role of Toll-like receptors in neuroimmune diseases: therapeutic targets and problems. Front Immunol 2021; 12:777606 [View Article] [PubMed]
     [Google Scholar]
  85. Heidari A, Yazdanpanah N, Rezaei N. The role of Toll-like receptors and neuroinflammation in Parkinson’s disease. J Neuroinflammation 2022; 19:135 [View Article] [PubMed]
     [Google Scholar]
  86. Gavegnano C, Detorio M, Montero C, Bosque A, Planelles V et al. Ruxolitinib and tofacitinib are potent and selective inhibitors of HIV-1 replication and virus reactivation in vitro. Antimicrob Agents Chemother 2014; 58:1977–1986 [View Article] [PubMed]
     [Google Scholar]
  87. Singer JW, Al-Fayoumi S, Ma H, Komrokji RS, Mesa R et al. Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor. J Exp Pharmacol 2016; 8:11–19 [View Article] [PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001858
Loading
IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia
J. Gen. Virol. 104, 001858 (2023); https://doi.org/10.1099/jgv.0.001858
/content/journal/jgv/10.1099/jgv.0.001858
/content/journal/jgv/10.1099/jgv.0.001858
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error