**7. Inflammation amplifier**

As described above, regional sensory neural activations transmit neural signals to sympathetic neurons, which then secrete norepinephrine at the target blood vessels to establish a gateway and recruit immune cells. Because chemokines have a critical role in immune cell recruitment, we hypothesized that machinery responsible for the production of chemokines could act as an interface between neural signals and immune reactions. Indeed, we discovered the inflam‐ mation amplifier, which is a local chemokine inducer. In this section, we describe the inflam‐ mation amplifier as a molecular mechanism for neuro‐immune interactions in blood vessels.

The Gateway Reflex, a Novel Neuro‐immune Interaction, is Critical for the Development of Mouse Multiple Sclerosis (MS) Models http://dx.doi.org/10.5772/62938 41

and physical/mental stresses. These physiological events too are often associated with MS symptoms [51]. Worsening of the clinical symptoms of neurological diseases including MS when the body is exposed to high ambient temperatures, called Uhthoff's phenomenon, is another well‐known example [52]. It is also known that stress burdens are associated with activation of the sympathetic nervous system, such as increased noradrenaline levels in the peripheral blood. Despite these correlations, a mechanical link between stress and disease development remains elusive. Neuronal activations, noradrenaline surge, and disease development are fundamental of the gateway reflex. Stress‐induced neural signals traveling to the CNS might modulate specific blood vessels depending on stress type, opening or closing a gateway for immune cells in the CNS. To examine this possibility, we have been testing the effects of various stresses on the pathogenesis of EAE. Although restraint stress and forced swim stress did not provoke EAE relapse [13], some stresses were found to worsen the clinical symptoms, whereas another stress prevented EAE development. These phenomena represent the fourth and fifth examples of the gateway reflex. The effects of good stress, or eustress, have also been reported in cancer models, in which tumor growth is delayed when mice are reared under an enriched environment with running wheels, tunnels, etc. in a larger cage [53, 54]. We suggest it may be possible to prevent diseases if stimulating the appropriate neurons can

Kevin Tracey and his colleagues have reported that activation of the vagus nerves, which mainly consist of parasympathetic nerves, leads to the suppression of systemic inflammation during septic shock in mice. This neural reflex is specifically called the "inflammatory reflex." In this context, lipopolysaccharide treatment in mice leads to norepinephrine release in the spleen via vagus and splenic nerves. A subset of T cells that receive norepinephrine signaling produces acetylcholine, which acts on macrophages to suppress the lipopolysaccharide‐ induced expression of inflammatory mediators such as TNFα [55], thus acting as a negative feedback system for excessive inflammatory reactions such as septic shock. It is also reported that electro‐acupuncture in mice at the ST36 Zusanli acupoint, which is located close to the common peroneal and tibial branches of the sciatic nerve, or directly to the sciatic nerve prevents a sepsis model through vagal activation and dopamine production [56]. A similar

As described above, regional sensory neural activations transmit neural signals to sympathetic neurons, which then secrete norepinephrine at the target blood vessels to establish a gateway and recruit immune cells. Because chemokines have a critical role in immune cell recruitment, we hypothesized that machinery responsible for the production of chemokines could act as an interface between neural signals and immune reactions. Indeed, we discovered the inflam‐ mation amplifier, which is a local chemokine inducer. In this section, we describe the inflam‐ mation amplifier as a molecular mechanism for neuro‐immune interactions in blood vessels.

trigger a good gateway reflex.

40 Trending Topics in Multiple Sclerosis

**7. Inflammation amplifier**

strategy may generate the gateway reflex in humans.

**Figure 4.** Inflammation amplifier. Simultaneous activation of the transcription factors NF‐κB and STATs creates a syn‐ ergistic effect on the production of inflammation mediators, such as chemokines, growth factors, and IL‐6, in nonim‐ mune cells, such as vascular endothelial cells and fibroblasts. Factors activating NF‐κB and STATs are various and include IL‐6, TNFα, and IL‐17. IL‐6 is expected to act on nonimmune cells to form a positive feedback loop that ampli‐ fies this synergistic effect. Massive chemokine and growth factor production by this mechanism, called the inflamma‐ tion amplifier, plays a central role in the pathogenesis of many inflammatory diseases and disorders.

To establish an IL‐6‐dependent autoimmune mouse model, we previously generated a knock‐ in mouse strain called F759 mice, which lacks the SOCS3 binding site of the IL‐6 signal transducer, gp130, thereby inhibiting SOCS3‐dependent negative signaling and excessive STAT3 activation [57]. Accordingly, F759 mice developed spontaneous rheumatoid arthritis‐ like joint disease and autoantibody production [58], which is consistent with the high levels of IL‐6 and clinical success of its signaling blockade in rheumatoid arthritis patients [59, 60]. Using these autoimmune‐prone F759 mice, we performed mechanistic analyses for the pathogenesis of their autoimmunity and found that IL‐6 signaling in nonimmune cells, such as vascular endothelial cells and fibroblasts, rather than immune cells, is important for the exaggerated inflammation [61, 62]. Mechanistically, coactivation of the transcription factors NF‐κB and STATs in nonimmune cells led to a synergistic production of inflammatory agents, including chemokines and growth factors, compared with NF‐κB or STAT activation alone (**Figure 4**). Factors that activate NF‐κB and STATs and therefore trigger the inflammation amplifier include IL‐17A, TNFα, IL‐22, IL‐6, and IFNγ. Furthermore, neurotransmitters, including 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 growth factors from nonimmune cells (**Figure 4**).

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.
