Gateway Reflex: A Neuro-Immune Crosstalk for Organ-Specific Disease Development

Abstract

Homeostasis of the central nervous system (CNS) is strictly regulated by a unique struc- ture of blood vessels, the blood-brain barrier (BBB). Experimental and clinical evidence has revealed that abnormalities in the BBB in chronic inflammatory diseases such as mul - tiple sclerosis (MS). By using an animal model of MS, we identified novel neuro-immune crosstalk to explain how pathogenic immune cells enter the CNS to disrupt its homeosta- sis, a phenomenon we named the gateway reflex. Regional neural inputs such as grav ity, electricity, pain or chronic stress cause specific neural activation to create a gateway of immune cells, particularly pathogenic ones, at specific blood vessels. Moreover, the recently discovered stress-induced gateway reflex uncovered a stress-induced neural link between the brain, gastrointestine, and heart. Thus, the gateway reflex is critical for the homeostasis of various organs, and aberrant activation of neural pathways by the gateway reflex disrupts normal organ homeostasis. The inflammatory reflex is another mechanism for local neuro-immune interactions. It potently exerts a cholinergic anti- inflammatory effect on various disease conditions. In this section, we discuss emerging roles for local neuro-immune interactions, with a special focus on the gateway reflex. sympathetic ganglion (4) and induces the activation of sympathetic nerves (5), which results in norepinephrine (NE) secretion (6) at the L5 dorsal vessels. NE enhances the inflammation amplifier in the L5 dorsal vessels, causing an upregulation of chemokines and recruiting pathogenic CD4+ T cells from the vessels (7).