Division of Molecular Neuroimmunology


Discovery of new gateway reflexes
Detailed investigation of reported gateway reflexes

 Genetic and environmental factors are involved in the development of autoimmune diseases. The genetic analysis of rare inherited autoimmune diseases directly showed the genes responsible for their development. Recently, a genome-wide association study (GWAS) to detect whole genome single nucleotide polymorphisms (SNPs) in patients with autoimmune diseases was performed using next-generation sequencing and reported many disease-associate genes. In addition, some environmental factors, such as ageing, infection and stress, are likely to worsen many of these diseases. We have conducted several studies focused on the cytokine IL-6 and CD4+ T cells. Among them, in 2008, we discovered the “IL-6 amplifier”, which is a hyper-induction machinery for inflammation and presented on non-immune cells, such as endothelial cells, fibroblastic cells, and exocrine cells. Many disease-associate genes are involved in the activation of the IL-6 amplifier via the NFkB signaling pathway, including NEDD4 and GTF2I. Moreover, we discovered a novel neuro-immune interaction, named the “Gateway Reflex”. In the Gateway Reflex, the activation of specific neural circuits triggered by several environmental factors leads to the secretion of noradrenaline at specific blood vessels to form gateways for autoreactive CD4+ T cells to enter the tissue, leading to the development of tissue-specific autoimmune diseases. In total, we have reported six Gateway Reflexes, in which a distinctive external stimulus (gravity, pain, stress, light, intra-articular inflammation, and artificial neuronal stimulation) induces the formation of the gateways to develop the tissue-specific inflammatory disease (Table below). In the Division of Molecular Neuroimmunology, we have studied these two novel concepts for the development of tissue-specific inflammation in collaboration with the Murakami laboratories at Hokkaido University and the National Institutes for Quantum Science and Technology. Regarding the Gateway Reflexes, we will clarify the responsible molecular and cellular mechanisms through
(1) the discovery of novel Gateway Reflexes,
(2) detailed analysis of the associated neural circuits,
(3) analysis of the molecular basis of the gateway formation, and
(4) analysis of the antigen specificity of autoreactive CD4+ T cells during the gateway formation.

IL-6 Amplifier and Gateway Reflex

Selected publications

*H. Ogura et al., Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity 29, 628-636 (2008).
*Y. Arima et al., Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell 148, 447-457 (2012).
*Y. Arima et al., Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit. eLife 6, (2017).
*M. Murakami, D. Kamimura, T. Hirano, Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines. Immunity 50, 812-831 (2019).
*R. Hasebe et al., ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons. The Journal of experimental medicine 219, (2022)