Potential Anti-inflammatory Treatment for Autism

Editor’s Note: We’re always on the lookout for new science that will help people living with autism. A recent paper by Theoharis Theoharides and colleagues has identified a possible treatment for the chronic neuroinflammatory state underlying many cases of autism. IL37 is an anti-inflammatory molecule of the immune system. It is increased in response to injury and protects the tissue from further inflammatory injury. Dr. Theoharides’ study found chronic inflammation in the brains of autistic children, confirming earlier studies. The brain areas included those involved in autism behaviors such as the amygdala. His study also found increased levels of IL37 in these areas, but notes that children with autism may not make enough IL37 to sufficiently suppress the neuroinflammation. IL37 treatment might increase levels sufficiently to reduce the inflammation.

IL37 is being explored for other immune-related diseases such as multiple sclerosis, colitis, and osteoarthritis. Scientists are actively pursuing methods to create IL37 for human therapeutics. We commend Dr. Theoharides for applying ideas in this exciting field to autism. Given the innovative nature of this work, SafeMinds invited Dr. Theoharides to write about his work and its implications for finding effective treatments for autistics. Dr. Theoharides runs the Laboratory of Molecular Immunopharmacology and Drug Discovery in the Department of Immunology at Tufts University School of Medicine, Boston. MA. We thank Dr. Theoharidis for his important contributions to the field over many decades.

See abstract for the paper. The full paper can be purchased for $10 from the publisher. The study is based on post-mortem analysis of 16 children age 3-14 years old, eight of whom had autism and eight who were typically developing.

IL-37 may be a novel biologic treatment for autism spectrum disorder

by Theoharis C. Theoharides, MS, MPhil, PhD, MD

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impaired social interactions and communication. 1 ASD affects about 1 in 59 children  2 and is estimated to reach 1 in 40 children in 2025. 3 The complexity of the factors involved in the clinical picture of ASD, along with the lack of reliable biomarkers 4 and specific pathogenesis 5 has prevented the development of effective treatments.

A number of authors have reported activation of microglia, the resident immune cells of the brain, in children with ASD 6,7,8 supporting the presence of inflammation in the brain. 9,10, 11 A number of inflammatory molecules, such as IL-1β, TNF and CXCL8, have been shown to be increased in the serum, cerebrospinal fluid (CSF) and brain of many patients with ASD. 12-14 We showed increased serum levels of IL-6 and TNF,14 as well as of mitochondrial DNA 15 and microRNA-155, 16 all of which cause inflammation which short-circuits the neuronal connectivity in the amygdala, which are important in behavioral processing.

We had previously reported increased levels of the brain protein neurotensin in the serum of children with ASD compared to non-ASD controls.17,18 Our laboratory further demonstrated that neurotensin stimulates gene expression and secretion of the pro-inflammatory cytokine IL-1β and the chemokine CXCL8 from cultured human microglia. 19We hypothesized that there may be some innate inhibitor of such an inflammatory response, and one possible candidate was the anti-inflammatory cytokine interleukin-37 (IL-37).

Interleukin-37 belongs to the IL-1 family of cytokines, and is a natural suppressor of inflammation. 20 In this report we investigated IL-37 gene expression in amygdala and dorsolateral prefrontal cortex of children with ASD because there is extensive evidence from animals and humans connecting the amygdala to social behavior. 21, 22 Moreover, amygdala communicate directly with the dorsolateral prefrontal cortex, which is important in behavioral processing. 23

We showed that IL-37 is increased along with the pro-inflammatory cytokine IL-18 and its receptor IL-18R, in the amygdala and dorsolateral prefrontal cortex of children with ASD. Moreover, IL-37 inhibits neurotensin-stimulated secretion and gene expression of IL-1β and CXCL8 from cultured human microglia. 24 These results suggest that the gene for IL-37 is activated in an effort to contain the inflammation in the amygdala, but the protein is either not produced or not made in sufficient amount to reduce the inflammation sufficiently.

The present findings provide a plausible pathogenetic process linking neurotensin to focal inflammation of the brain. Use of IL-37 could have a major advantage over drugs targeting IL-1β because IL-37 could inhibit secretion of not only IL-1β, but other pro-inflammatory cytokines and chemokines. IL-37 could, therefore, be developed as a novel treatment approach for ASD.

This work was funded by an anonymous donation. We are in desperate need for more funding to investigate the effect of the different five analogues of IL-37 found in nature and formulate the most potent analogue in a form that could be delivered intranasaly to enter the brain through the olfactory nerve path.  We believe,that, given enough resources, IL-37 could be the first effective biologic treatment for ASD.

Reference List

  1. Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet 2014; 383(9920):896-910.
  2. Centers for Disease Control and Prevention. CDC estimates 1 in 59 children has been identified with autism spectrum disorder.4-30-2018.  https://www.cdc.gov/features/new-autism-data/index.html.
  3. Leigh JP, Du J. Brief Report: Forecasting the Economic Burden of Autism in 2015 and 2025 in the United States. J Autism Dev Disord 2015; 12:4135-4139.
  4. Ruggeri B, Sarkans U, Schumann G, Persico AM. Biomarkers in autism spectrum disorder: the old and the new. Psychopharmacology (Berl) 2014; 231(6):1201-1216.
  5. Theoharides TC, Doyle R, Francis K, Conti P, Kalogeromitros D. Novel therapeutic targets for autism. Trends Pharmacol Sci 2008; 29(8):375-382.
  6. Patel AB, Tsilioni I, Leeman SE, Theoharides TC. Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc Natl Acad Sci U S A 2016; 113:E7049-E7058.
  7. Gupta S, Ellis SE, Ashar FN et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun 2014; 5:5748.
  8. Koyama R, Ikegaya Y. Microglia in the pathogenesis of autism spectrum disorders. Neurosci Res 2015; 100:1-5.
  9. Rossignol DA, Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol 2014; 5:150.
  10. Theoharides TC, Tsilioni I, Patel AB, Doyle R. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry 2016; 6(6):e844.
  11. Theoharides TC, Kavalioti M, Tsilioni I. Mast Cells, Stress, Fear and Autism Spectrum Disorder. Int J Mol Sci 2019; 20(15).
  12. Zimmerman AW, Jyonouchi H, Comi AM et al. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol 2005; 33(3):195-201.
  13. Li X, Chauhan A, Sheikh AM et al. Elevated immune response in the brain of autistic patients. J Neuroimmunol 2009; 207(1-2):111-116.
  14. Tsilioni I, Taliou A, Francis K, Theoharides TC. Children with Autism Spectrum Disorders, who improved with a luteolin containing dietary formulation, show reduced serum levels of TNF and IL-6. Transl Psychiatry 2015; 5:e647.
  15. Zhang B, Angelidou A, Alysandratos KD et al. Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. J Neuroinflammation 2010; 7(1):80.
  16. Almehmadi K.A., Tsilioni, Theoharides T.C. Increased expression of miR-155p5 in amygdala of children with Autism Spectrum Disorder. Autism Res 2019.
  17. Angelidou A, Francis K, Vasiadi M et al. Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflam 2010; 7:48.
  18. Tsilioni I, Dodman N, Petra AI et al. Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism. Transl Psychiatry 2014; 4:e466.
  19. Patel AB, Tsilioni I, Leeman SE, Theoharides TC. Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc Natl Acad Sci U S A 2016; 113:E7049-E7058.
  20. Dinarello CA, Bufler P. Interleukin-37. Semin Immunol 2013; 25(6):466-468.
  21. Bauman ML, Kemper TL. The neuropathology of the autism spectrum disorders: what have we learned? Novartis Found Symp 2003; 251:112-122.
  22. Bliss-Moreau E, Moadab G, Santistevan A, Amaral DG. The effects of neonatal amygdala or hippocampus lesions on adult social behavior. Behav Brain Res 2017; 322(Pt A):123-137.
  23. Bicks LK, Koike H, Akbarian S, Morishita H. Prefrontal Cortex and Social Cognition in Mouse and Man. Front Psychol 2015; 6:1805.
  24. Tsilioni I, Patel A.B., Pantazopoulos H et al. 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.

Further Reading

Inflammation and autism—an important piece of the puzzle.

Inflammation may be main driver of autism, find scientists who studied the brains of eight children on the spectrum who had died

Interleukin-37: A crucial cytokine with multiple roles in disease and potentially clinical therapy.

Mast Cells May Regulate The Anti-Inflammatory Activity of IL-37.

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