Early-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling.
Yee Ming KhawDanish MajidSungjong OhEunjoo KangMakoto InouePublished in: Nature communications (2021)
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.
Keyphrases
- multiple sclerosis
- early life
- mass spectrometry
- high fat diet induced
- white matter
- ms ms
- cell proliferation
- signaling pathway
- newly diagnosed
- end stage renal disease
- ejection fraction
- chronic kidney disease
- type diabetes
- insulin resistance
- metabolic syndrome
- prognostic factors
- combination therapy
- skeletal muscle
- risk assessment
- immune response
- trauma patients
- drug induced
- binding protein
- smoking cessation
- patient reported