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The Gate Theory Explains Regional Neural Regulation of Activated T cells Entering the Central Nervous System

Daisuke Kamimura, Moe Yamada, Lavannya Sabharwal, Hideki Ogura, Yuko Okuyama, Akihiro Nakamura, Toru Atsumi, Yasunobu Arima and Masaaki Murakami

Type 17 helper T (Th17) cells are a subset of activated CD4⁺ T cells that produce interleukin (IL)-17 and contribute to the pathogenesis of autoimmune diseases via inflammation induction. Th17 differentiation is induced by T cell receptor engagement in the presence of several cytokines including IL-1β, IL-23, TGF-β and IL-6. IL-6 is often elevated during inflammation and chronic inflammatory diseases such as autoimmune disorders. We have shown that a combination of IL-17 and IL-6 synergistically induces the production of target molecules including various chemokines and IL-6 itself in non-immune cells such as fibroblasts and endothelial cells. We named this phenomenon the “inflammation amplifier” and determined it essential for the induction of chronic inflammatory diseases. Moreover, our results showed that the inflammation amplifier describes simultaneous activation of NF-κB and STAT3, with the major signal being NF-κB, and STAT3 acting as a costimulatory signal that enhances the expression of NF-κB targets. Thus, the inflammation amplifier can be viewed as a NF-κB loop in non-immune cells that establishes the inflammation status via local chemokine expression. It was recently shown that activation of the inflammation amplifier in blood vessel endothelium is enhanced by regional neural stimuli and results in local upregulation of chemokines and subsequent immune cell infiltration and pathogenic CD4⁺ T cells. Thus, a gate for immune cells from the blood to the site of inflammation, including regions like the central nervous system (CNS), can be opened or closed by regional neuronal stimulations across our entire body. We name this phenomenon the gate theory. In this review article, we summarize our recent data, discuss the physiology of the inflammation amplifier, and gate theory in various inflammatory diseases.