Inflammation is critical for the development of many complex diseases and disorders. Inflammation comes in two types: chronic inflammation, which can be defined as a dysregulated form of inflammation, and acute inflammation, which can defined as a regulated form. Because of its special role in the aforementioned diseases, establishing methods to control chronic inflammation is important for developing cures and treatments against various diseases and disorders. One challenge to achieve this has been the ability to distinguish chronic and acute inflammation based on molecular biology diagnostics. Thus, our research is focused on two subjects, which aim to control the chronic inflammation, which is involved in various diseases and disorders including autoimmune diseases, neurodegenerative diseases, metabolic syndromes, other inflammatory diseases, and cancers.

Regulation of Chronic Inflammation by Neuro-Immune Cross Talks.

The central nervous system (CNS) is considered an immune-privileged tissue protected by a specific vessel structure, the blood-brain barrier (BBB). Upon infection or traumatic injury in the CNS, the BBB is breached, and various immune cells are recruited to the affected area. In the case of autoimmune diseases in the CNS like multiple sclerosis (MS), autoreactive T cells against some CNS-specific antigens can theoretically attack neurons throughout the CNS. The affected CNS regions in MS patients can be detected as multiple focal plaques in the cerebrum, thoracic cord, and other regions. Vision problems are often associated with the initial phase of MS, suggesting a disturbance in the optic nerves. These observations raise the possibility that there exist specific signals that direct autoreactive T cells past the BBB and into particular sites of the CNS. Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we recently defined the mechanism of the pathogenesis in which regional neural stimulations modulate the status of the blood vessel endothelium to allow the invasion of autoreactive T cells into specific sites of the CNS via the fifth lumbar cord. Moreover, this gate for autoreactive T cells can be artificially manipulated by removing gravity forces on the hind legs or by electric pulses to the soleus muscles, quadriceps, and triceps of mice, resulting in an accumulation of autoreactive T cells in the intended regions via the activation of regional neurons. Gating blood vessels by regional neural stimulations, a phenomenon we call the gateway theory, has potential therapeutic value not only in preventing autoimmunity, but also in augmenting the effects of cancer immunotherapies.

Analysis of The Inflammation Amplifier, A Molecular Mechanism of Chronic Inflammation Development

IL-6 is a cytokine expressed by various activated cells including CD4+ cells and has an important role in the development of inflammation. It is also required for the development of Th17 cells, which are IL-17-expressing activated CD4+ T cells and strongly correlates with various inflammatory disease models. We previously identified the inflammation amplifier (formerly the IL-6 amplifier) as a fundamental mechanism of inflammation induction in such disease models as well as in human inflammatory diseases. The amplifier, which is activated by simultaneous stimulation of NF-kB and STAT3 via cytokines such as IL-17A and IL-6 in type 1 collagen+ non-immune cells, induces a positive feedback loop of IL-6. The amplifier acts as a local chemokine inducer that accumulates various immune cells followed by the local dysregulation of homeostasis, i.e. inflammation. Since its discovery, we have shown that the amplifier is hyper-activated by various factors including cytokines, neurotransmitters, and the growth factors. We recently combined two genome-wide mouse screens with SNP-based disease association studies, GWAS, revealing 1,700 genes related to the inflammation amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases to analyze if the amplifier is involved in human diseases and disorders. We followed up on epiregulin-ErbB1 pathway from our list. Blocking ErbB1 signaling suppressed the inflammation amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases including rheumatoid arthritis, multiple sclerosis, and arteriosclerosis. These results indicate that the inflammation amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets. Therefore, we have been investigating the regulators of the inflammation amplifier to establish new approaches for the chromic

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