Gateway Reflex and Mechanotransduction

Abstract

The gateway reflex explains how autoreactive CD4+ T cells cause inflammation in tissues that have blood-barriers, such as the central nervous system and retina. It depends on neural activations in response to specific external stimuli, such as gravity, pain, stress, and light, which lead to the secretion of noradrenaline at specific vessels in the tissues. Noradrenaline activates NFkB at these vessels, followed by an increase of chemokine expression as well as a reduction of tight junction molecules to accumulate autoreactive CD4+ T cells, which breach blood-barriers. Transient receptor potential vanilloid 1 (TRPV1) molecules on sensory neurons are critical for the gateway reflex, indicating the importance of mechano-sensing. In this review, we overview the gateway reflex with a special interest in mechanosensory transduction (mechanotransduction).

Keywords: CD4+ T cells; gateway reflex; inflammation; mechanotransduction; tissue specific autoimmune diseases.

Figure 1

Mechano-sensing receptors in endothelial cells. An illustration showing multiple mechano-sensing receptors, including mechanosensory ion channels and adhesion molecules, that can respond to extracellular stimulations, such as pressure, gravity, acceleration, sound, tension, fluid flow, pain, light, temperature, and blood pressure, to induce mechanotransduction in endothelial cells. The sensors shown include tyrosine kinase receptors (TK R), G protein-coupled receptors, ion channels, junction proteins, integrins, the cell membrane (caveolae), and glycocalyx.

Figure 2

Light gateway reflex. The light gateway reflex. Photopic light stimulates a high expression of noradrenaline and adrenaline to downregulate a1A-adrenoceptor (a _1AAR) expression on the retinal vessels in mice with autoreactive T cells against photoreceptors. The downregulation of a_1AAR inhibits the noradrenaline-mediated activation of NFκB and STAT3, suppressing the IL-6 amplifier and retinal inflammation.

Figure 3

Gravity gateway reflex. Gravity stimulation induces the activation of sensory nerves in the soleus muscles, which connects the fifth lumbar vertebra (L5) dorsal root ganglion, followed by the activation of L5 sympathetic ganglion neurons. Norepinephrine (also known as noradrenaline) from the sympathetic nerves induces the IL-6 amplifier and the infiltration of autoreactive T cells into the spinal cord by upregulating CCL20 at the dorsal vessels of the L5 cord.

Figure 4

Pain gateway reflex. Pain-induced sensory nerve activation stimulates the anterior cingulate cortex (ACC), which activates specific sympathetic nerves distributed at two ventral vessels of the spinal cord. Because there are many major histocompatibility complex (MHC) class II⁺ monocytes around the L5 cord, norepinephrine secretion at the ventral blood vessels of the fifth lumbar vertebra (L5) cord stimulates the production of CX3CL1 from endothelial cells via the IL-6 amplifier. CX3CL1 accumulates MHC class II⁺ monocytes and increases the permeability of blood vessels. Autoreactive T cells in the blood flow accumulate at the vessels to induce experimental autoimmune encephalomyelitis relapse.

Figure 5

Stress gateway reflex. Chronic stresses including light sleep activate noradrenergic neurons in the paraventricular nucleus (PVN) to establish gateways for immune cells at specific blood vessels in the brain, particularly in the presence of myelin-specific CD4⁺ T cells in the blood. Myelin-specific CD4⁺ T cells accumulate at the specific vessels together with major histocompatibility complex class II⁺ monocytes to develop micro-inflammation there. ATP produced by the micro-inflammation functions as a neurotransmitter to directly activate neurons in the dorsomedial hypothalamic nucleus (DMH)/anterior hypothalamic nucleus (AHN), followed by the activation of neurons of the dorsal motor vagal nucleus (DMX). The resulting activated efferent vagus nerve causes acetylcholine-dependent gastrointestinal inflammation followed by hyperkalemia with heart failure and sudden death.