2017/9/25

Chronic stress induces fatal organ dysfunctions via a new...

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Chronic stress induces fatal organ dysfunctions via a new neural circuit

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New research reveals the mechanisms behind the effects of chronic stress and tiny inflammations in the brain
on fatal gut failure.

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Hokkaido University researchers revealed that fatal gut
failure in a multiple sclerosis (MS) mouse model, EAE,
under chronic stress is caused by a newly discovered nerve
pathway. The findings could provide a new therapeuticstrategy for the intractable disease, particularly progressive
MS, which has no therapeutic strategy at present.

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MS affects an estimated 2.5 million people worldwide andcauses motor dysfunction, impaired vision andgastrointestinal failures. It is an autoimmune condition of thecentral nervous system (CNS) mediated by immune cells
called autoreactive CD4+ T cells. In EAE mouse models,these pathogenic CD4+ T cells can cause a MS­like disease
when transfused intravenously to healthy mice.

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In previous studies using EAE mouse models, Professor
Masaaki Murakami of Hokkaido University and hiscolleagues revealed autoreactive CD4+ T cells cross the blood­brain barrier at specific sites and cause inflammation inthe CNS including the brain and spinal cord. The emergence of a “gateway” for autoreactive CD4+ T cells to cross thebarrier was caused by regional neural activation at those sites, which is triggered by specific sensory­sympatheticinteractions. They termed these phenomena as gateway reflexes and have published on at least three, the gravity­,electric­, and pain­gateway reflexes.
In the present study, the team and their collaborators in Japan and Germany investigated the possible relations between
chronic stress, micro­inflammation in the brain, and stress­related organ failures.
They put healthy mice under stress by disturbing their sleep or by rearing them on wet bedding. The transfer ofpathogenic CD4+ T cells under the stress caused severe symptoms such as gastrointestinal failures and even sudden
death. Cell transfer or stress alone did not cause these symptoms. Subsequent investigations revealed a complex nerve­
related mechanism behind this process.
The injected pathogenic CD4+ T cells accumulated around blood vessels in two specific sites at the center of the brainsof the stressed mice. Micro­inflammation developed around specific blood vessels, and the inflamed sites then released asmall molecule called ATP that switched on a nerve pathway that is normally turned off. This switch led to gut
dysfunctions, bleeding and failure. Also, the bleeding led to increased levels of potassium in the blood, which was one offactors leading to heart failure.
The team was able to prevent gut failure by suppressing inflammation in the brain or blocking nerve pathways from thebrain to the gut. The results suggest that tiny areas of inflammation around some specific vessels in the brain, which are
known to happen in various brain diseases including multiple sclerosis, are a risk factor for organ dysfunctions including
severe gut and heart failure.
“These results demonstrate a direct link between brain micro­inflammation and fatal gastrointestinal diseases via theestablishment of a new neural pathway under stress,” says Masaaki Murakami. “Micro­inflammation in the brain is also
seen in Alzheimer’s disease and Parkinson’s disease. So it’s of particular interest to investigate possible connections
between brain micro­inflammations and organ dysfunctions, including those within the brain itself, in those patients.”
The study was published in the journal eLife.
Original article:
Arima Y., et al. Brain micro­inflammation at specific vessels dysregulates organ­homeostasis via the activation of a newneural circuit. eLIFE. August 15, 2017.
DOI: 10.7554/eLife.25517
Contacts:
Professor Masaaki Murakami
Institute for Genetic Medicine
Hokkaido University
Email: murakami@igm.hokudai.ac.jp
Naoki Namba (Media Officer)
Global Relations OfficeInstitute for International Collaboration
Hokkaido University
Tel: +81­11­706­2185
Email: pr[at]oia.hokudai.ac.jp
Associated links
Hokkaido University press release
Research paper
Journal information
Arima Y., et al. Brain micro­inflammation at specific vessels dysregulates organ­homeostasis via the activation of a newneural circuit. eLIFE. August 15, 2017.
DOI: 10.7554/eLife.25517

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Chronic stress induces fatal organ dysfunctions via a new...
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