Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit

Abstract

Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.DOI: http://dx.doi.org/10.7554/eLife.25517.001

Neural stimulations regulate the infiltration of immune cells into the CNS

“…Surprisingly, stressed EAE mice died suddenly without showing tail tip paralysis, a typical initial symptom of transfer EAE due to neuroinflammation from the L5 spinal cord by the gravity gateway reflex. No death occurred by chronic stress or transfer EAE alone . Autopsy of the dead mice revealed severe epithelial damages and bleeding in the upper gastrointestine.…”

“…gateway reflex). Neutralization of CCL5 successfully prevented immune cell accumulation around the vessels and mortality in stressed EAE mice, suggesting that CCL5‐induced inflammation in the brain‐specific vessels was critical for the mortality .…”

“…We found that the DMH region was highly activated in stressed EAE mice but not in mice with stress or EAE alone, although PVN neurons particularly noradrenergic ones were activated in mice with stress alone. Experiments using neural tracers identified direct neural connections between the brain‐specific vessels and the PVN or DMH region . Namely, the stress response was enhanced by the presence of micro‐inflammation around the brain‐specific vessels most likely via the identified neural connections.…”

“…It is also known that ATP is extracellularly secreted from endothelial cells after cytokine stimulation. The intracranial injection of a P2RX7 antagonist at the brain‐specific vessels decreased neural activation of the DMH region and prevented mortality in stressed EAE mice, suggesting ATP mediates neural activations between the specific vessels and DMH . DMH neurons are known to connect to the DMX, and hyperactivation of the vagus nerve pathway is associated with epithelial damage in the stomach via an acetylcholine‐mediated overproduction of gastric acid , which was observed in stressed EAE mice .…”

Targeting molecules involved in immune cell trafficking to the central nervous system for therapy in multiple sclerosis

“…14 We have also found a direct molecular link between regional brain micro-inflammation and unexpected peripheral organ dysfunctions through specific neural pathways under stress conditions. 41 These results suggested that regional neural activations define a gateway for immune cells at specific blood vessels (gateway reflex) by chemokine expression, and that stress-mediated neural activations can disrupt these reflexes to cause organ dysfunctions (Fig. 2).…”