**Acknowledgements**

norepinephrine and several growth factors, augment the amplifier by enhancing NF‐κB activation [12, 63]. Since chemokines can recruit immune cells and promote inflammation, we named this synergistic mechanism in nonimmune cells the "inflammation amplifier" [64, 65]. Mice lacking gp130 or STAT3 in type 1 collagen+ cells including various nonimmune cells were highly resistant to animal models of rheumatoid arthritis, MS, and chronic graft rejection via suppression of the regional accumulation of immune cells [12, 13, 62, 63, 66, 67]. The inflam‐ mation amplifier is also seen in astrocytes, resulting in the development of EAE [68]. In addition, we found evidence of the inflammation amplifier activation in human clinical specimens, and human disease‐associated genes are highly enriched in inflammation ampli‐ fier‐related genes according to genome‐wide RNA functional screening [67]. These data suggested that the inflammation amplifier is a critical mechanism for the development of various inflammatory diseases via excessive expression of inflammatory chemokines and

Subsequent studies about the gateway reflex demonstrated that neural signals translate into inflammatory signals by the inflammation amplifier in target vascular endothelial cells. In the case of the gravity‐mediated gateway reflex, neural signals from the soleus muscles reached the L5 dorsal vessel endothelium via sensory‐sympathetic cross talk, where norepinephrine from the activated sympathetic neurons excessively stimulated the inflammation amplifier by increasing NF‐κB activity to secrete various NF‐κB‐targets including chemokines. Moreover, the L5 but not L1 dorsal vessel endothelium showed activation of STAT3. Pharmacological inhibition of beta‐adrenergic receptors suppressed NF‐κB activation, chemokine production, and pathogenic CD4+ T‐cell accumulation in the L5 dorsal vessels and EAE development [12]. Similarly, during the pain‐mediated gateway reflex, treatment with a beta‐adrenergic receptor antagonist resulted in no accumulation of activated monocytes or pathogenic CD4+ T cells around the target dorsal vessels of the L5 spinal cord. Neutralization of cytokines that activate the inflammation amplifier such as IL‐6 and IL‐17A also suppressed the pain‐induced EAE relapse and pathogenic CD4+ T‐cell accumulation [13]. These results indicate that the inflam‐ mation amplifier is a foundation of the immunological response induced by the gateway reflex.

The CNS is an immune‐privileged site protected by the BBB, but the gateway reflex, which can be triggered by various neural stimulations, can induce gateways for immune cells to circumvent the BBB. So far, three kinds of gateway reflex have been identified: gravity, elec‐ tric stimulation, and pain‐induced, all of which involve sensory‐sympathetic communica‐ tion. Further study of the mechanisms driving the gateway reflex should consider the neural network involved and whether it is present in other organs and tissues. Newly developed imaging techniques and tools including a tissue decolorization reagent, CUBIC [69, 70], will help elucidate the former. For the latter, it is recently reported there exists barrier architec‐ ture with similar components to the BBB in the gut endothelium, the so‐called gut‐vascular barrier [22]. A similar system may explain how immune cells breach this barrier. Because neuronal circuits run throughout the body, the gateway reflex could have a tremendous

growth factors from nonimmune cells (**Figure 4**).

**8. Future directions**

42 Trending Topics in Multiple Sclerosis

We thank the excellent assistance by Ms. Chiemi Nakayama, Ms. Mitsue Ezawa and Ms. Satomi Fukumoto (Hokkaido University, Sapporo, Japan), and Dr. Peter Karagiannis for reading the manuscript. This work was supported by KAKENHI (D. K., Y. A., T. A., and M. M.), Takeda Science Foundation (M. M. and D. K.), Institute for Fermentation Osaka (M. M.), Mitsubishi Foundation (M. M.), Uehara Memorial Foundation (M. M.), Mochida Memorial Foundation for Medical and Pharmaceutical Research (D. K.), Suzuken Memorial Foundation (D. K. and Y. A.), Japan Prize Foundation (Y. A.), Ono Medical Research Foundation (Y. A.), Kanzawa Medical Research Foundation (Y. A.), Kishimoto Foundation (Y. A.), Nagao Takeshi Research Foundation (Y. A.), Tokyo Medical Research Foundation (M. M. and Y. A.), JSPS Postdoctoral Fellowship for Foreign Researchers (A.S.), JST‐CREST program (M. M.), and the Osaka Foundation for the Promotion of Clinical Immunology (M. M.). The authors declare they have no conflicting financial interests.
