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.
Highlights
Environmental triggers have important functions in multiple sclerosis (MS) susceptibility, phenotype, and trajectory
We use C57BL/6J mice and the experimental autoimmune encephalitis (EAE) model to demonstrate that early life trauma (ELT) induces increases in severity and susceptibility in EAE and induces a phenotype shift characterized by interferon-β insensitivity, neuronal damage in the spinal cord, in addition to membrane-bound lymphotoxin and CXCR2 involvement
To examine if the condition of ELT is necessary to provoke severe disease, we compared disease severity of control EAE mice against EAE mice subjected to maternal separation or sterile phosphate-buffered saline (PBS) injection alone
Summary
Environmental triggers have important functions in multiple sclerosis (MS) susceptibility, phenotype, and trajectory. ELTsubjected 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. 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. We use C57BL/6J mice and the experimental autoimmune encephalitis (EAE) model to demonstrate that ELT induces increases in severity and susceptibility in EAE and induces a phenotype shift characterized by interferon-β insensitivity, neuronal damage in the spinal cord, in addition to membrane-bound lymphotoxin and CXCR2 involvement. Our results indicate that phenotype changes in mice subjected to ELT can be explained by downregulated adrenergic signaling in immune cells
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