Outlines

A research team of the Graduate School of Medicine, The University of Osaka, including Specially Appointed Assistant Professor Yumiko Mizuno, Department of Respiratory Medicine and Clinical Immunology, Researcher Hiroaki Matsushita, Joint Research Course for the Center for Medical Innovation and Translational Research, and President Atsushi Kumanogoh (Professor of Department of Respiratory Medicine and Clinical Immunology, at the time of research) has, for the first time in the world, discovered that semaphorin 6D (Sema6D), a molecule produced in vascular endothelial cells, regulates the number of sympathetic nerves and serves as a key factor in ensuring proper immune function under cold environment (Fig. 1).

Although autoimmune diseases such as rheumatoid arthritis and multiple sclerosis are known to worsen in cold environments, its detailed mechanisms have remained unclear.

In this study, the research group found that when Sema6D is absent in vascular endothelial cells, sympathetic nerves become excessively abundant. As a result, it was found that sympathetic nerves become excessively activated under cold environment, leading to tissue hypoxia and impaired immune function.

These results clarified one of the mechanisms through which environmental temperature affects autoimmune disease progression, and they are expected to advance further research on temperature and immune responses as well as the development of new approaches for disease control.

Fig. 1. Sema6D in vascular endothelial cells properly regulates the distribution of sympathetic nerves and maintains immune responses under cold environment
Credit: Yumiko Mizuno

Research Background

It has been known that cold environments increase susceptibility to infections and can worsen autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. It is also known that cold environments activate the sympathetic nervous system, which mediates the body’s stress response. However, the detailed mechanisms by which sympathetic nerve distribution regulates immune responses under cold environment have remained unclear.

Research Content

The research group has elucidated a mechanism in which Sema6D, a molecule produced in vascular endothelial cells, regulates the positioning of sympathetic nerves and regulates immune responses under cold environment. In the absence of Sema6D in vascular endothelial cells, sympathetic nerves became excessively distributed in the lymph nodes, leading to increased norepinephrine (NE) levels under cold environment and resulting in tissue hypoxia. Furthermore, in the absence of Sema6D in vascular endothelial cells, immune cell activation was suppressed under cold environment, and the severity of paralysis induced experimentally was reduced compared with the control group. At room temperature, however, the degree of paralysis was similar to that observed in the control group.

Moreover, pharmacological inhibition of sympathetic nerve activity revealed that excessive sympathetic activation is the cause of immune suppression under cold environment. These findings show that neurovascular coordination mediated by Sema6D plays a crucial role in regulating immune responses under cold environments.

Social Impact

The study results are expected to deepen the understanding of why symptoms of autoimmune diseases tend to worsen in winter. In the future, these findings may lead to the development of new therapeutic strategies targeting neurovascular interactions, and they also open the possibility of applying sympathetic‑nerve–mediated immune regulation to the treatment of various immune‑related diseases.

Notes

The article, “Endothelial semaphorin 6D controls immune responses under cold stress through regulation of sympathetic innervation,” was published in American scientific journal of The Journal of Immunology (Online) at DOI: https://doi.org/10.1080/23294515.2025.2474928.