Neural Stimulations Modulate the Formation of Immune Cell Gateways into the CNS Masaaki Murakami Division of Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
The blood-brain barrier (BBB) controls the exchanges of substances and the migration of immune cells to the central nervous system (CNS). Despite the BBB, immune cell can enter the CNS even at the steady state. We found a mechanism operated by a specific local neuroimmune interaction that explains how autoreactive CD4+ T cells transverse the BBB to invade the CNS, which is termed the gateway reflex. The gateway reflex is induced by the activation of specific sensory-sympathetic neural pathways by various stimulations including gravity, electric, pain, and chronic stress etc, which enhance chemokine expressions at specific vessels and establishes specific gateways for autoreactive CD4+ T cells in the blood stream toward the CNS. Mechanistic analysis showed that norepinephrine and cytokines at the specific vessels induce a simultaneous activation of NFkB and STAT3 followed by enhanced expression of various NFkB targets including chemokines to establish the gateway of immune cells in the BBB. While these gateways are localized at the vessels of the fifth lumbar spinal cord at the steady state due to stimulation by gravity, the location can vary with the type of sensory stimulations. Recently, we unexpectedly found that chronic stress-mediated neural activation changes the location of immune cell gateway to the specific blood vessels of the brain, followed by a fatal dysregulation in the gastrointestine and heart. I will discuss the discovery and recent advances about the gateway reflexes.