Neural activity regulates autoimmune diseases through the gateway reflex

Abstract

The brain, spinal cord and retina are protected from blood-borne compounds by the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB) and blood-retina barrier (BRB) respectively, which create a physical interface that tightly controls molecular and cellular transport. The mechanical and functional integrity of these unique structures between blood vessels and nervous tissues is critical for maintaining organ homeostasis. To preserve the stability of these barriers, interplay between constituent barrier cells, such as vascular endothelial cells, pericytes, glial cells and neurons, is required. When any of these cells are defective, the barrier can fail, allowing blood-borne compounds to encroach neural tissues and cause neuropathologies. Autoimmune diseases of the central nervous system (CNS) and retina are characterized by barrier disruption and the infiltration of activated immune cells. Here we review our recent findings on the role of neural activity in the regulation of these barriers at the vascular endothelial cell level in the promotion of or protection against the development of autoimmune diseases. We suggest nervous system reflexes, which we named gateway reflexes, are fundamentally involved in these diseases. Although their reflex arcs are not completely understood, we identified the activation of specific sensory neurons or receptor cells to which barrier endothelial cells respond as effectors that regulate gateways for immune cells to enter the nervous tissue. We explain this novel mechanism and describe its role in neuroinflammatory conditions, including models of multiple sclerosis and posterior autoimmune uveitis.

Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex

“…The pro-inflammatory cytokines IL-6 and IL-17A are known to play a crucial role in the pathogenesis of EAU [ 67 ]. These cytokines synergistically activate NF-κB and STAT3, resulting in enhanced expression of inflammatory chemokines in endothelial cells to recruit immune cells across the BBB or BRB into the central nervous system or retina, respectively [ 22 , 23 , 24 , 25 , 26 , 27 ]. Based on our previous study [ 21 ], we hypothesized that the protective effect of L-DOPA on suppressing the recruitment of immune cells into the retina could be mediated by the inhibition of NF-κB and STAT3 activity in the BRB endothelium.…”

“…This neurogenic mechanism is termed the gateway reflex, and its molecular basis is the inflammation amplifier, a positive feedback loop between pro-inflammatory cytokines IL-6 and IL-17, and transcription factors STAT3 and NF-κB. The inflammation amplifier maintains a persistent and massive expression of a variety of chemokines, cytokines, and growth factors by non-immune cells like endothelial cells, thereby promoting recruitment of immune cells in affected tissues [ 22 , 23 , 24 , 25 , 26 , 27 ]. Importantly, the ability of the photopic light-mediated neural activity (the light gateway reflex) to suppress the inflammation amplifier in retinal endothelial cells reduced immune cell entry in the retina and the progression of experimental autoimmune uveoretinitis (EAU) [ 21 ], a murine model of autoimmune posterior uveitis/panuveitis [ 28 , 29 ].…”

Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB

“…Actually, it has been reported that nanocarriers modified on the surface by anti-ICAM-1 or VCAM-1 showed a higher uptake in an inflamed brain compared to non-targeted nanocarriers [ 182 , 183 , 184 , 185 ]. Other reports have proposed “the gateway theory” [ 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 ]. According to these reports, there is a gateway by which pathogens or immune cells enter the CNS, and the mechanism of gateway formation is a massive chemokine-inducing “inflammation amplifier” through the co-activation of the NF-kB and STAT3 pathways [ 187 , 191 ].…”

Childhood Obesity, Endothelial Cell Activation, and Critical Illness

“…Neurogenically, endothelial function is modulated by the “gateway reflex,” or neural circuits regulating entry of immune cells to the CNS by modulating the vascular EC barrier. The gateway reflex phenomenon also contributes to recruitment of immune cells to other tissues ( 16 ).…”