Toll-like Receptors in Autism Spectrum Disorder
Abstract
Autism Spectrum Disorder (ASD) is a multifaceted neurodevelopmental condition characterized by diverse behavioral and cognitive challenges. Despite its rising prevalence, the underlying mechanisms remain inadequately understood. Toll-like receptors (TLRs), as critical components of the innate immune system, are implicated in neuroinflammatory processes that may contribute to the pathogenesis of ASD. This narrative review delves into the relationship between TLRs and ASD. Notably, studies reveal an upregulation of TLR4 and TLR2 expression in B cells and placental tissues of individuals with ASD, correlating with increased levels of pro-inflammatory cytokines such as IL-6 and TNF-alpha. Maternal immune activation (MIA), particularly due to infections during pregnancy, has been shown to trigger TLR-mediated inflammatory responses that adversely affect fetal brain development. For instance, maternal cytomegalovirus (CMV) infection leads to heightened expression of TLR4/2 in the placenta, resulting in significant placental inflammation and altered neurodevelopmental trajectories in offspring. Furthermore, evidence indicates that individuals with ASD exhibit impaired immune responses characterized by dysfunctional natural killer (NK) cells and monocytes, which produce excessive pro-inflammatory cytokines upon TLR4 stimulation but show diminished responses to TLR9 ligands. This immune dysregulation is associated with a shift towards a TH2 cytokine profile, complicating the understanding of immune phenotype correlations with ASD symptom severity. Additionally, TLR3 activation by viral RNA has been linked to behavioral changes in murine models, underscoring the potential for maternal infections to influence neurodevelopment through TLR signaling pathways. These findings illuminate the role of TLRs in ASD pathophysiology and suggest that targeting TLR pathways may offer novel therapeutic avenues for intervention in this complex disorder.
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3. Salari N, Rasoulpoor S, Rasoulpoor S, Shohaimi S, Jafarpour S, Abdoli N, et al. The global prevalence of autism spectrum disorder: a comprehensive systematic review and meta-analysis. Italian Journal of Pediatrics. 2022;48(1):1-16.
4. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature immunology. 2001;2(8):675-80.
5. Delneste Y, Beauvillain C, Jeannin P. Innate immunity: structure and function of TLRs. Medecine Sciences: M/S. 2007;23(1):67-73.
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8. Al-Harbi NO, Nadeem A, Ahmad SF, Al-Ayadhi LY, Al-Harbi MM, Sobeai HMA, et al. Elevated expression of toll-like receptor four is associated with NADPH oxidase-induced oxidative stress in B cells of children with autism. International Immunopharmacology. 2020;84:106555.
9. Liao Y, Zhang YN, Liu XL, Lu YY, Zhang LL, Xi T, et al. Maternal Murine Cytomegalovirus Infection during Pregnancy Up-regulates the Gene Expression of Toll-like Receptors 2 and 4 in Placenta. Curr Med Sci. 2018;38(4):632-9.
10. Kawai T, Akira S, editors. TLR signaling. Seminars in immunology; 2007: Elsevier.
11. Brennan JJ, Gilmore TD. Evolutionary Origins of Toll-like Receptor Signaling. Molecular Biology and Evolution. 2018;35(7):1576-87.
12. O'neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nature Reviews Immunology. 2013;13(6):453-60.
13. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34(5):637-50.
14. Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity. 2010;32(3):305-15.
15. Celhar T, Magalhaes R, Fairhurst A-M. TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunologic research. 2012;53(1):58-77.
16. Lee BL, Moon JE, Shu JH, Yuan L, Newman ZR, Schekman R, et al. UNC93B1 mediates differential trafficking of endosomal TLRs. elife. 2013;2.
17. Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, Crozat K, et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7, and 9. Nature immunology. 2006;7(2):156-64.
18. Takahashi K, Shibata T, Akashi-Takamura S, Kiyokawa T, Wakabayashi Y, Tanimura N, et al. A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses. The Journal of Experimental Medicine. 2007;204(12):2963-76.
19. Fukui R, Saitoh S-i, Matsumoto F, Kozuka-Hata H, Oyama M, Tabeta K, et al. Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA but against RNA-sensing. Journal of Experimental Medicine. 2009;206(6):1339-50.
20. Garcia-Cattaneo A, Gobert F-X, Müller M, Toscano F, Flores M, Lescure A, et al. Cleavage of Toll-like receptor three by cathepsins B and H is essential for signaling. Proceedings of the National Academy of Sciences. 2012;109(23):9053-8.
21. Park B, Brinkmann MM, Spooner E, Lee CC, Kim Y-M, Ploegh HL. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nature immunology. 2008;9(12):1407-14.
22. Majewska M, Szczepanik M. The role of Toll-like receptors (TLR) in innate and adaptive immune responses and their function in immune response regulation. Postepy Higieny i Medycyny Doswiadczalnej (Online). 2006;60:52-63.
23. Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA, et al. Maternal immune activation and abnormal brain development across CNS disorders. Nature Reviews Neurology. 2014;10(11):643-60.
24. Han VX, Jones HF, Patel S, Mohammad SS, Hofer MJ, Alshammery S, et al. Emerging evidence of Toll-like receptors as a putative pathway linking maternal inflammation and neurodevelopmental disorders in human offspring: A systematic review. Brain Behav Immun. 2022;99:91-105.
25. Warren RP, Foster A, Margaretten NC. Reduced natural killer cell activity in autism. Journal of the American Academy of Child & Adolescent Psychiatry. 1987;26(3):333-5.
26. Enstrom AM, Onore CE, Van de Water JA, Ashwood P. Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain, behavior, and immunity. 2010;24(1):64-71.
27. Warren RP, Margaretten NC, Pace NC, Foster A. Immune abnormalities in patients with autism. Journal of autism and developmental disorders. 1986;16:189-97.
28. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J. Altered T cell responses in children with autism. Brain Behav Immun. 2011;25(5):840-9.
29. Plioplys AV, Greaves A, Kazemi K, Silverman E. Lymphocyte function in autism and Rett syndrome. Neuropsychobiology. 1994;29(1):12-6.
30. Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. Journal of Experimental Medicine. 2010;207(5):1067-80.
31. Gupta S, Aggarwal S, Rashanravan B, Lee T. Th1-and Th2-like cytokines in CD4+ and CD8+ T cells in autism. Journal of Neuroimmunology. 1998;85(1):106-9.
32. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain, behavior, and immunity. 2011;25(1):40-5.
33. Atladóttir HÓ, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdallah M, et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. Journal of autism and developmental disorders. 2010;40:1423-30.
34. Brown AS. Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Developmental neurobiology. 2012;72(10):1272-6.
35. Matelski L, Van de Water J. Risk factors in autism: Thinking outside the brain. Journal of autoimmunity. 2016;67:1-7.
36. Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nature Reviews Neuroscience. 2015;16(8):469-86.
37. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783-801.
38. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature. 2001;413(6857):732-8.
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| Files | ||
| Issue | Vol 7, No 4 (2024) | |
| Section | Review Article | |
| DOI | https://doi.org/10.18502/igj.v7i4.17889 | |
| Keywords | ||
| Autism Spectrum Disorder oll-Like Receptors Innate Immune System Immunology Neurodevelopmental Disorder | ||
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How to Cite
1.
Kazemzadeh K. Toll-like Receptors in Autism Spectrum Disorder. Immunol Genet J. 2024;7(4):246-259.
