The Issue of Monocyte Activation in ASD: Troubles with Translation.

Autism spectrum disorder (ASD) prevalence has increased year on year for the past two decades and currently affects 1 in 44 individuals in the US. An increasing number of studies have pointed to increased immune activation as both an etiological agent and also involved in the ongoing pathological process of ASD. Both adaptive and innate immune responses have been implicated. Evidence of innate dysregulation has so far included increased production of innate inflammatory cytokines, increased cell numbers, and altered activation in monocytes in the blood and microglia in the brain. Suggesting an orchestrated innate immune response may be involved in ASD. Hughes et al. (2022) recently assessed transcriptome differences that could underlie altered activation of monocytes using next-generation bulk-RNA sequencing on isolated CD14+ monocytes at baseline and after activation with different Toll-like receptor agonists. Circulating CD14+ monocyte from children with autistic disorder (AD) and children diagnosed with perverse developmental disorder not otherwise specified (PDD-NOS) were found to differ in a number of activation pathways after gene enrichment analysis compared to typically developing children. There was an overall upregulation in translational machinery in both neurodevelopmental disorder groups, whereas typically developing children were downregulated, indicating an issue with monocyte activation. Several identified differentially expressed genes in monocytes were also identified as ASD at-risk genes, according to the Simons Foundation Autism Research Initiative (SFARI), and genes involved in inflammatory bowel diseases. This work implicates altered monocyte activation with a lack of regulation as a potential mechanistic issue in ASD. Future work is warranted to evaluate how monocyte regulatory mechanisms differ in ASD individuals.