Early-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling.

Autor:	Khaw YM; University of Illinois at Urbana-Champaign Department of Comparative Biosciences, 2001 South Lincoln Avenue, Urbana, IL, 61802, USA.; University of Illinois at Urbana-Champaign Neuroscience Program, 405 North Matthews Avenue, Urbana, IL, 61801, USA., Majid D; University of Illinois at Urbana-Champaign Department of Comparative Biosciences, 2001 South Lincoln Avenue, Urbana, IL, 61802, USA.; University of Illinois at Urbana-Champaign School of Molecular and Cell Biology, 407 South Goodwin Avenue, Urbana, IL, 61801, USA., Oh S; University of Illinois at Urbana-Champaign Department of Comparative Biosciences, 2001 South Lincoln Avenue, Urbana, IL, 61802, USA.; University of Illinois at Urbana-Champaign School of Molecular and Cell Biology, 407 South Goodwin Avenue, Urbana, IL, 61801, USA., Kang E; University of Illinois at Urbana-Champaign Department of Comparative Biosciences, 2001 South Lincoln Avenue, Urbana, IL, 61802, USA.; University of Illinois at Urbana-Champaign Neuroscience Program, 405 North Matthews Avenue, Urbana, IL, 61801, USA., Inoue M; University of Illinois at Urbana-Champaign Department of Comparative Biosciences, 2001 South Lincoln Avenue, Urbana, IL, 61802, USA. makotoi@illinois.edu.; University of Illinois at Urbana-Champaign Neuroscience Program, 405 North Matthews Avenue, Urbana, IL, 61801, USA. makotoi@illinois.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2021 Jan 04; Vol. 12 (1), pp. 105. Date of Electronic Publication: 2021 Jan 04.
DOI:	10.1038/s41467-020-20302-0
Abstrakt:	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.
Databáze:	MEDLINE
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