Early-life-trauma Triggers Interferon-β Resistance and Neurodegeneration in a Multiple Sclerosis Model Via Downregulated β1-adrenergic Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jan 5

PMID 33397973

Citations 6

Authors

Yee Ming Khaw

Danish Majid

Sungjong Oh

Eunjoo Kang

Makoto Inoue

Affiliations

Soon will be listed here.

Abstract

Environmental triggers have important functions in multiple sclerosis (MS) susceptibility, phenotype, and trajectory. Exposure to early life trauma (ELT) has been associated with higher relapse rates in MS patients; however, the underlying mechanisms are not well-defined. Here we show ELT induces mechanistic and phenotypical alterations during experimental autoimmune encephalitis (EAE). ELT sustains downregulation of immune cell adrenergic receptors, which can be attributed to chronic norepinephrine circulation. ELT-subjected mice exhibit interferon-β resistance and neurodegeneration driven by lymphotoxin and CXCR2 involvement. These phenotypic changes are observed in control EAE mice treated with β1 adrenergic receptor antagonist. Conversely, β1 adrenergic receptor agonist treatment to ELT mice abrogates phenotype changes via restoration of immune cell β1 adrenergic receptor function. Our results indicate that ELT alters EAE phenotype via downregulation of β1 adrenergic signaling in immune cells. These results have implications for the effect of environmental factors in provoking disease heterogeneity and might enable prediction of long-term outcomes in MS.

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References

Hunter S . Overview and diagnosis of multiple sclerosis. Am J Manag Care. 2016; 22(6 Suppl):s141-50. View

Quintana F, Farez M, Viglietta V, Iglesias A, Merbl Y, Izquierdo G . Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis. Proc Natl Acad Sci U S A. 2008; 105(48):18889-94. PMC: 2596207. DOI: 10.1073/pnas.0806310105. View

Lassmann H, Bruck W, Lucchinetti C . Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med. 2001; 7(3):115-21. DOI: 10.1016/s1471-4914(00)01909-2. View

Disanto G, Berlanga A, Handel A, Para A, Burrell A, Fries A . Heterogeneity in multiple sclerosis: scratching the surface of a complex disease. Autoimmune Dis. 2011; 2011:932351. PMC: 3005811. DOI: 10.4061/2011/932351. View

Cepok S, Zhou D, Srivastava R, Nessler S, Stei S, Bussow K . Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest. 2005; 115(5):1352-60. PMC: 1077174. DOI: 10.1172/JCI23661. View

Ascherio A, Munger K, Simon K . Vitamin D and multiple sclerosis. Lancet Neurol. 2010; 9(6):599-612. DOI: 10.1016/S1474-4422(10)70086-7. View

Hedstrom A, Baarnhielm M, Olsson T, Alfredsson L . Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology. 2009; 73(9):696-701. DOI: 10.1212/WNL.0b013e3181b59c40. View

Ghadirian P, Dadgostar B, Azani R, Maisonneuve P . A case-control study of the association between socio-demographic, lifestyle and medical history factors and multiple sclerosis. Can J Public Health. 2002; 92(4):281-5. PMC: 6979686. View

Ghadirian P, Jain M, Ducic S, Shatenstein B, Morisset R . Nutritional factors in the aetiology of multiple sclerosis: a case-control study in Montreal, Canada. Int J Epidemiol. 1998; 27(5):845-52. DOI: 10.1093/ije/27.5.845. View

10.

Nisipeanu P, Korczyn A . Psychological stress as risk factor for exacerbations in multiple sclerosis. Neurology. 1993; 43(7):1311-2. DOI: 10.1212/wnl.43.7.1311. View

11.

Spitzer C, Bouchain M, Winkler L, Wingenfeld K, Gold S, Grabe H . Childhood trauma in multiple sclerosis: a case-control study. Psychosom Med. 2012; 74(3):312-8. DOI: 10.1097/PSY.0b013e31824c2013. View

12.

Dube S, Fairweather D, Pearson W, Felitti V, Anda R, Croft J . Cumulative childhood stress and autoimmune diseases in adults. Psychosom Med. 2009; 71(2):243-50. PMC: 3318917. DOI: 10.1097/PSY.0b013e3181907888. View

13.

Manni L, Micera A, Pistillo L, Aloe L . Neonatal handling in EAE-susceptible rats alters NGF levels and mast cell distribution in the brain. Int J Dev Neurosci. 1998; 16(1):1-8. DOI: 10.1016/s0736-5748(98)00003-3. View

14.

Meagher M, Sieve A, Johnson R, Satterlee D, Belyavskyi M, Mi W . Neonatal maternal separation alters immune, endocrine, and behavioral responses to acute Theiler's virus infection in adult mice. Behav Genet. 2010; 40(2):233-49. PMC: 2862313. DOI: 10.1007/s10519-010-9333-5. View

15.

Stephan M, Straub R, Breivik T, Pabst R, von Horsten S . Postnatal maternal deprivation aggravates experimental autoimmune encephalomyelitis in adult Lewis rats: reversal by chronic imipramine treatment. Int J Dev Neurosci. 2002; 20(2):125-32. DOI: 10.1016/s0736-5748(02)00007-2. View

16.

Columba-Cabezas S, Iaffaldano G, Chiarotti F, Alleva E, Cirulli F . Early handling increases susceptibility to experimental autoimmune encephalomyelitis (EAE) in C57BL/6 male mice. J Neuroimmunol. 2009; 212(1-2):10-6. DOI: 10.1016/j.jneuroim.2009.05.007. View

17.

Cattaneo A, Macchi F, Plazzotta G, Veronica B, Bocchio-Chiavetto L, Riva M . Inflammation and neuronal plasticity: a link between childhood trauma and depression pathogenesis. Front Cell Neurosci. 2015; 9:40. PMC: 4379909. DOI: 10.3389/fncel.2015.00040. View

18.

Khulan B, Manning J, Dunbar D, Seckl J, Raikkonen K, Eriksson J . Epigenomic profiling of men exposed to early-life stress reveals DNA methylation differences in association with current mental state. Transl Psychiatry. 2014; 4:e448. PMC: 4203020. DOI: 10.1038/tp.2014.94. View

19.

Huang Q, Tang H, Teo S, Mok D, Ritchie S, Nath A . Neonatal genetics of gene expression reveal potential origins of autoimmune and allergic disease risk. Nat Commun. 2020; 11(1):3761. PMC: 7387553. DOI: 10.1038/s41467-020-17477-x. View

20.

Danese A, Lewis S . Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?. Neuropsychopharmacology. 2016; 42(1):99-114. PMC: 5143500. DOI: 10.1038/npp.2016.198. View