**6. Other gateway reflexes**

**Figure 3.** Pain‐mediated gateway reflex. Pain‐induced sensory neuron activation results in the activation of specific sympathetic neurons that control norepinephrine (NE) expression around the ventral vessels of every level of the spi‐ nal cords. This system is regulated by the anterior cinculate cortex (ACC) in the brain. Because the fifth lumbar (L5) spinal cord abundantly contains MHC class II high activated monocytes, this region is affected significantly during pain sensation. NE from pain‐specific sympathetic neurons at the ventral vessels induces the production of CX3CL1 from the activated monocytes, further recruiting these cells in an auto/paracrine manner. The MHC class II high acti‐ vated monocytes are able to present MOG antigens to pathogenic CD4+ T cells, which in turn activate the inflamma‐

During the first episode of EAE, MOG‐reactive CD4+ T cells enter the CNS from the dorsal vessels of the L5 spinal cord [12]. The transferred CD4+ T cells are then found at the upper levels of the spinal cord and brain, which matches typical clinical manifestations of EAE including the initial tail tip weakness and subsequent ascending paralysis. Intriguingly, after pain induction in apparently normal EAE‐recovered mice, the relapse also starts from the loss of tonicity of the tail tip, suggesting that the L5 cord could again be a gateway for relapse. However, an immunohistochemical examination of the L5 spinal cord from EAE‐recovered mice showed differences with naïve mice, with many MHC class II high monocytes around the meningeal region. After pain induction, these cells accumulated at the L5 ventral vessels, but not dorsal vessels within a day. This accumulation is dependent on a chemokine CX3CL1, which is secreted from the MHC class II high monocytes themselves and astrocytes after norepinephrine stimulation. Therefore, the pain‐mediated gateway reflex induces norepi‐ nephrine secretion from sympathetic neurons around the L5 ventral vessels and subsequent auto/paracrine induction of CX3CL1 followed by MHC class II high monocyte accumulations. Because these monocytes are able to present MOG peptides, circulating MOG‐reactive pathogenic CD4+ T cells can recognize the L5 ventral vessels as an entry site to the CNS. Indeed, a depletion of CD4+ T cells including pathogenic ones from EAE‐recovered mice abrogated the clinical symptoms of EAE relapse (i.e. paralysis), but the accumulation of MHC class II high monocytes around the L5 ventral vessels remained intact. These results suggested that the activated monocyte accumulation is an upstream event relative to pathogenic CD4+ T‐cell

tion amplifier (Amp) in regional endothelial cells and subsequently cause a relapse in the disease.

38 Trending Topics in Multiple Sclerosis

invasion and required for EAE relapse induced by pain sensation [13].

In addition to the sensory perceptions described above, including gravity‐, electric stimula‐ tion‐, and pain‐mediated stimuli, neural excitations occur in response to emotional alterations 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 trigger a good gateway reflex.

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 strategy may generate the gateway reflex in humans.
