Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 7 4 2024 12 22 246 259 Kimia Kazemzadeh Network of Neurosurgery and Artificial Intelligence (NONAI), Universal Scientific Education and Research Network (USERN), Tehran, Iran 2025 02 17 2025 02 17 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. https://igj.tums.ac.ir/index.php/igj/article/view/187 https://igj.tums.ac.ir/index.php/igj/article/download/187/160