Summary: In a mouse study, early-life stress increased the likelihood of developing autoimmune disease resembling multiple sclerosis and reduced responsiveness to a common therapy.
Source: University of Illinois
Childhood trauma alters disease course and treatment response in a mouse model of multiple sclerosis, a new study finds.
Researchers at the University of Illinois Urbana-Champaign report that mice exposed to stress in early life were more likely to develop experimental autoimmune encephalomyelitis (EAE), the standard animal model for multiple sclerosis (MS), and showed poorer responses to interferon beta, a widely used initial MS therapy. The study also identifies a potential way to reverse those effects by targeting a specific immune-cell receptor.
Multiple sclerosis is an autoimmune, neurodegenerative condition in which the immune system attacks the myelin sheath that insulates nerve fibers, producing a variety of neurological symptoms. Both inherited factors and environmental exposures, including early-life adversity, have been linked to MS risk and clinical variability.
Previous clinical and epidemiological work has suggested that childhood trauma and early-life stress increase the risk of more severe MS, but the biological mechanisms were not well understood. In the new study, published in Nature Communications, the Illinois team led by Makoto Inoue used genetically susceptible mice to investigate how early-life trauma (ELT) affects disease susceptibility, progression, and treatment responsiveness in EAE.
To model early-life stress, researchers briefly separated pups from their mother and administered a saline injection during a sensitive developmental window. They then compared these ELT-exposed mice with control mice that did not experience the same early stress. The investigators followed disease onset, motor symptoms, and neurological damage, and examined immune signaling pathways linked to stress hormones.
“Mice that experienced early-life trauma were more prone to developing EAE and endured prolonged motor paralysis and marked neuronal damage in the central nervous system,” said graduate student Yee Ming Khaw, the study’s first author. “Those differences were driven by an exaggerated immune response that we traced to altered adrenergic signaling.”
Specifically, the team identified changes in immune cells’ β1-adrenergic receptor, which responds to the stress hormone norepinephrine. Early-life stress caused sustained elevations in circulating norepinephrine, leading to prolonged activation and subsequent downregulation of the receptor on immune cells. Reduced receptor expression left the immune system less able to regulate inflammation, promoting neuroinflammation and tissue damage during EAE.
Importantly, the researchers found that EAE developed after early-life stress was resistant to interferon beta treatment, while the same therapy effectively prevented disease progression in mice without early stress exposure. This finding suggests that childhood trauma can create a distinct disease phenotype that responds differently to standard MS treatments.
To address that resistance, the investigators tested a compound that enhances β1-adrenergic receptor signaling on immune cells. Treatment with this receptor agonist prevented paralysis and reduced spinal cord damage in ELT-exposed mice. Moreover, mice that received the receptor-targeting compound became responsive to interferon beta, despite their prior lack of response.
“Our results indicate that individuals with a history of childhood trauma may develop autoimmune disease with different underlying mechanisms and clinical features compared with those without such history, and they may require different therapeutic strategies,” said Makoto Inoue. The study authors propose that boosting β1-adrenergic signaling could be explored as a therapeutic avenue for MS patients who experienced early-life trauma.
The research team plans further work to confirm the receptor’s mechanistic role and to carry out translational studies testing whether enhancing this pathway in people with MS and a history of childhood adversity produces similar benefits as seen in the mouse model.
“We believe the best approach for individuals with autoimmune disease and a background of childhood trauma is a comprehensive, personalized treatment plan that considers both biological and psychosocial factors,” Inoue added.
Funding: This research was supported by the University of Illinois and the Sumitomo Foundation.
About this multiple sclerosis research news
Source: University of Illinois
Contact: Liz Ahlberg Touchstone – University of Illinois
Image: The image is in the public domain
Original Research: Open access. “Early-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling” by Yee Ming Khaw, Danish Majid, Sungjong Oh, Eunjoo Kang & Makoto Inoue. Nature Communications
Abstract
Early-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling
Environmental factors strongly influence multiple sclerosis susceptibility, clinical phenotype, and disease course. Early-life trauma has been associated with higher relapse rates in people with MS, but the mechanisms remain unclear. In this study, early-life trauma induced sustained downregulation of β1-adrenergic receptors on immune cells in a mouse model of EAE, driven by chronic elevations of norepinephrine. Mice exposed to early-life trauma developed interferon-β resistance and increased neurodegeneration, processes linked to lymphotoxin and CXCR2 signaling. Similar phenotypic changes were reproduced in control mice treated with a β1-adrenergic receptor antagonist, while treatment with a β1-adrenergic receptor agonist restored receptor function and reversed the phenotype in trauma-exposed mice. These findings suggest that early-life trauma alters immune regulation via β1-adrenergic signaling and may help explain disease heterogeneity in MS, with potential implications for predicting outcomes and tailoring therapies.