Toll-like Receptors in Autism Spectrum Disorder

Abstract

Autism Spectrum Disorder (ASD) is a multifaceted neurodevelopmental condition characterized by diversebehavioral and cognitive challenges. Despite its rising prevalence, the underlying mechanisms remain in-adequately understood. Toll-like receptors (TLRs), as critical components of the innate immune system, areimplicated in neuroinflammatory processes that may contribute to the pathogenesis of ASD. This narrativereview delves into the relationship between TLRs and ASD. Notably, studies reveal an upregulation of TLR4and TLR2 expression in B cells and placental tissues of individuals with ASD, correlating with increasedlevels 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 inflammatoryresponses 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 in-flammation and altered neurodevelopmental trajectories in offspring. Furthermore, evidence indicates thatindividuals with ASD exhibit impaired immune responses characterized by dysfunctional natural killer(NK) cells and monocytes, which produce excessive pro-inflammatory cytokines upon TLR4 stimulationbut show diminished responses to TLR9 ligands. This immune dysregulation is associated with a shift to-wards a TH2 cytokine profile, complicating the understanding of immune phenotype correlations with ASDsymptom severity. Additionally, TLR3 activation by viral RNA has been linked to behavioral changes inmurine models, underscoring the potential for maternal infections to influence neurodevelopment throughTLR signaling pathways. These findings illuminate the role of TLRs in ASD pathophysiology and suggestthat targeting TLR pathways may offer novel therapeutic avenues for intervention in this complex disorder.