Aberrant IL-17 Levels in Rodent Models of Autism Spectrum Disorder: A Systematic Review

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterised by stereotyped behaviours, specific interests, and impaired communication skills. Elevated levels of pro-inflammatory cytokines, such as interleukin-17A (IL-17A or IL-17), have been implicated as part of immune alterations that may contribute to this outcome. In this context, rodent models have helped elucidate the role of T-cell activation and IL-17 secretion in the pathogenesis of ASD. Regarding the preclinical findings, the data available is contradictory in offspring but not in the pregnant dams, pointing to IL-17 as one of the main drivers of altered behaviour in some models ASD, whilst there are no alterations described in IL-17 levels in others. To address this gap in the literature, a systematic review of altered IL-17 levels in rodent models of ASD was conducted. In total, 28 studies that explored IL-17 levels were included and observed that this cytokine was generally increased among the different models of ASD. The data compiled in this review can help the choice of animal models to study the role of cytokines in the development of ASD, seeking a parallel with immune alterations observed in individuals with this condition.Systematic Review RegistrationPROSPERO, identifier CRD42022306558.

Gestational hypothyroxinemia induces ASD-like phenotypes in behavior, proinflammatory markers, and glutamatergic protein expression in mouse offspring of both sexes

“…The increased serum concentration of proinflammatory cytokines in the HTX-offspring is in concordance with ASD-like molecular features. Considering the neuroinflammatory component of ASD ( 47 ), IL-17A and its counterpart IL-10 were quantified in brain regions related to social cognition (prefrontal cortex (PFC) and hippocampus) ( Figure 7 , Supplementary Table 2-2.2 ). In the PFC, both female and male HTX-offspring had an increased concentration of IL-17A ( Figure 7A , Supplementary Table 2-2.2a ), while a reduction of IL-10 in the PFC was only observed in male HTX-offspring, compared to Control and HTX+T 4 offspring ( Figure 7B , Supplementary Table 2-2.2b ).…”

“…Consistently, anti-inflammatory cytokines like IL-10 and TGF-β1 are typically lower in ASD patients ( 45 , 46 ). Additionally, elevated concentration of IL-17A in specific brain regions, which is considered as a neuroinflammatory-like trait, is associated with alterations in social cognition and appears to be a signature outcome of ASD physiopathology according to animal models displaying ASD-like behaviors ( 47 ). Moreover, ASD-related inflammatory profile can be accompanied by persistent dysregulation of both innate and adaptive immune response, as indicated by murine models.…”

Gestational hypothyroxinemia causes autistic-like behaviors, increases proinflammatory traits, and alters glutamatergic protein expression in mouse adult offspring of both sexes.

“…Subsequently, and taking into consideration the association between neuroinflammatory traits and neurodevelopmental disorders [48,49], we quantified IL-17A and its counterpart IL-10 in the prefrontal cortex (PFC) and hippocampus of each experimental group (see Materials and methods) (Figure 7, SF 2.2), which are pivotal brain regions for social cognition and organization control [47,48]. In the PFC, we found that HTX-offspring (both sexes) had an increased concentration of IL-17A (Fig.…”

Combination of machine learning-based bulk and single-cell genomics reveals necroptosis-related molecular subtypes and immunological features in autism spectrum disorder

“…Males are notably more likely to develop ASD than females (3). Recent studies have proven that genetics, inflammatory response, oxidative stress, and hypoxic insult exert crucial roles in leading to ASD progression (4)(5)(6)(7). The specific pathological mechanisms underlying ASD remain largely unexplored.…”