Brain micro-inflammation at specific vessels creates a new neural pathway, which induces the dysregulation of the gastrointestinal homeostasis under stress conditions
Mitsutoshi Ota1, Yasunobu Arima1, Takuto Ohki1, Yuki Tanaka1, Daisuke Kamimura1, Masaaki Murakami1*
1Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University
It is well known that chronic stresses exacerbate illness such as gastrointestinal failure. However, its molecular mechanism remains poorly understood. At this conference, we show one of the underlying mechanisms by using an adoptive transfer system of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. EAE mice typically develop tail and hind limb paralysis, but the symptom is not lethal. However, under chronic stress conditions, EAE mice showed high mortality, associated with severe gastrointestinal failure. Interestingly, while donor pathogenic CD4+ T cells specific for a myelin antigen accumulated at the fifth lumbar spinal cord in mice under normal condition, the stress condition directed them to intrude at the specific vessels of boundary area of the third ventricle, thalamus, and dentate gyrus to establish brain micro-inflammation. Importantly, instead of EAE induction, brain micro-inflammation at specific vessels induced by direct cytokine injection was sufficient to establish severe gastrointestinal failure in mice with stress. Resulting brain micro-inflammation activated the specific neural pathway including the paraventricular nucleus (PVN), dorsomedial nucleus of hypothalamus (DMH), and vagal neurons to cause severe gastrointestinal failure. In contrast, suppression of the brain micro-inflammation or blockage of the neural pathway inhibited the organ failure and improved mortality. These results showed a direct link between brain micro-inflammation and gastrointestinal homeostasis via a specific neural pathway under stress conditions. We therefore suggest that brain micro-inflammation(s) could act as a switch to activate the new neural pathway(s) to regulate organ homeostasis.