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

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

Author information

1
Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, MA 02111.
2
Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111.
3
Translational Neuroscience Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA 02478.
4
Immunology Division, Postgraduate Medical School, University of Chieti, 65100 Pescara, Italy.
5
Department of Pharmacology, Boston University School of Medicine, Boston, MA 02118; sleeman@bu.edu theoharis.theoharides@tufts.edu.
6
Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, MA 02111; sleeman@bu.edu theoharis.theoharides@tufts.edu.
7
Department of Internal Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111.

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

PMID:
31591201
PMCID:
PMC6815178
[Available on 2020-04-07]
DOI:
10.1073/pnas.1906817116

Conflict of interest statement

Competing interest statement: T.C.T. is the inventor of US patents no. 7,906,153; no. 8,268,365, and no. 9,050,275 for the treatment of autism and neuroinflammatory conditions.

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