Impact of early like trauma on murine multiple sclerosis phenotype and development via dysregulated 1 adrenergic signaling

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. Using C57BL/6J mice, we show that ELT induces mechanistic and phenotypical alterations during experimental autoimmune encephalitis (EAE). ELT induces not only increases in severity and susceptibility in EAE but also induces a phenotype shift characterized by interferon-β insensitivity, severe neuronal damage in the spinal cord, in addition to membrane-bound lymphotoxin and CXCR2 involvement. To understand how ELT induces phenotype change in EAE development, we assessed sympathetic adrenergic neuron activity in immune cells of ELT mice. Using flow cytometry, we found that immune cell adrenergic receptors are chronically downregulated in ELT mice, attributable to chronic norepinephrine circulation. ELT-mediated EAE 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 may enable prediction of outcomes in MS.