IL-37 is increased in brains of children with autism spectrum disorder and inhibits human microglia stimulated by neurotensin

Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21659-21665. doi: 10.1073/pnas.1906817116. Epub 2019 Oct 7.

Abstract

Autism spectrum disorder (ASD) does not have a distinct pathogenesis or effective treatment. Increasing evidence supports the presence of immune dysfunction and inflammation in the brains of children with ASD. In this report, we present data that gene expression of the antiinflammatory cytokine IL-37, as well as of the proinflammatory cytokines IL-18 and TNF, is increased in the amygdala and dorsolateral prefrontal cortex of children with ASD as compared to non-ASD controls. Gene expression of IL-18R, which is a receptor for both IL-18 and IL-37, is also increased in the same brain areas of children with ASD. Interestingly, gene expression of the NTR3/sortilin receptor is reduced in the amygdala and dorsolateral prefrontal cortex. Pretreatment of cultured human microglia from normal adult brains with human recombinant IL-37 (1 to 100 ng/mL) inhibits neurotensin (NT)-stimulated secretion and gene expression of IL-1β and CXCL8. Another key finding is that NT, as well as the proinflammatory cytokines IL-1β and TNF increase IL-37 gene expression in cultured human microglia. The data presented here highlight the connection between inflammation and ASD, supporting the development of IL-37 as a potential therapeutic agent of ASD.

Keywords: IL-37; autism spectrum disorder; brain; inflammation; neurotensin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Amygdala / metabolism*
  • Autism Spectrum Disorder / metabolism*
  • Cells, Cultured
  • Child
  • Humans
  • Interleukin-1 / metabolism*
  • Interleukin-18 / metabolism
  • Interleukin-18 Receptor alpha Subunit / metabolism
  • Interleukin-1beta / biosynthesis
  • Interleukin-8 / biosynthesis
  • Microglia / metabolism*
  • Neurotensin / metabolism*
  • Prefrontal Cortex / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Adaptor Proteins, Vesicular Transport
  • CXCL8 protein, human
  • IL18R1 protein, human
  • IL1B protein, human
  • IL37 protein, human
  • Interleukin-1
  • Interleukin-18
  • Interleukin-18 Receptor alpha Subunit
  • Interleukin-1beta
  • Interleukin-8
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Neurotensin
  • sortilin