Neural stimulations regulate the infiltration of immune cells into the CNS

Abstract

The systemic regulation of immune reactions by the nervous system is well studied and depends on the release of hormones. Some regional regulations of immune reactions, on the other hand, depend on specific neural pathways. Better understanding of these regulations will expand therapeutic applications for neuroimmune and organ‐to‐organ functional interactions. Here, we discuss one regional neuroimmune interaction, the gateway reflex, which converts specific neural inputs into local inflammatory outputs in the CNS. Neurotransmitters released by the inputs stimulate specific blood vessels to express chemokines, which serve as a gateway for immune cells to extravasate into the target organ such as the brain or spinal cord. Several types of gateway reflexes have been reported, and each controls distinct CNS blood vessels to form gateways that elicit local inflammation, particularly in the presence of autoreactive immune cells. For example, neural stimulation by gravity creates the initial entry point to the CNS by CNS‐reactive pathogenic CD4+ T cells at the dorsal vessels of fifth lumbar spinal cord, while pain opens the gateway at the ventral side of blood vessels in the spinal cord. In addition, it was recently found that local inflammation by the gateway reflex in the brain triggers the activation of otherwise resting neural circuits to dysregulate organ functions in the periphery including the upper gastrointestinal tract and heart. Therefore, the gateway reflex represents a novel bidirectional neuroimmune interaction that regulates organ functions and could be a promising target for bioelectric medicine.

Interleukin-1 receptor-induced PGE2 production controls acetylcholine-mediated cardiac dysfunction and mortality during scorpion envenomation

“…Some studies confirm that electrical stimulation of the vagus nerve controls exacerbated inflammatory responses 33 , such as in rheumatoid arthritis and Crohn’s disease 34 , 35 . Other neuroimmune pathways and bioelectronics approaches involving autonomic signaling have been studied in inflammatory conditions 36 – 38 . In contrast, other studies have demonstrated that autonomic dysfunctions are involved in the pathophysiology of different immunosuppressed and cardiovascular conditions mediated by neuroimmune circuits.…”

An integrated cytokine and kynurenine network as the basis of neuroimmune communication

“…Changes of CNS function can be induced by depleting peripheral CD4 + T cells ( Bauer et al, 2007 ; Wolf et al, 2009 ; Kipnis et al, 2012 ). This leads to hippocampal neuronal loss and reduced cognition which is prevented by IL-4, indicating that neuronal viability and functional integrity are maintained by immune mediators secreted by peripheral lymphocytes ( Kipnis et al, 2012 ; Kamimura and Murakami, 2019 ). Many such influences are probably mediated by the itinerant leukocyte populations passing through the CNS parenchyma.…”

“…It has been suggested that the level of local neural activity influences cytokine production and receptor expression which then generate a differential attraction of immune system cells into the CNS, further linking neural activity with neuroimmune communication ( Kamimura and Murakami, 2019 ). Such a mechanism could well be a factor in refining these concepts.…”

Bioelectronic medicine: an unexpected path to new therapies

“…Recent data indicate that specific sensory nerves control the permeability of the blood–brain barrier at specific locations and may thus control the entry of immune cell populations into the central nervous system . Kamimura & Murakami in this issue describe a ‘ gateway reflex ’ in which sensory input through specific neural conduits regulates chemokine expression and blood–brain‐barrier integrity in ways that control immune cell entry into the CNS.…”