1: Pulmonary arterial hypertension caused by AhR signal activation protecting against colitis.

American Journal of Respiratory and Critical Care Medicine.

2020 October 14; doi: 10.1126/science.abb4853.

Takahiro Hiraide, Toshiaki Teratani, Shizuka Uemura, Yusuke Yoshimatsu, Makoto Naganuma, Yoshiki Shinya, Mizuki Momoi, Eiji Kobayashi, Yoji Hakamata, Keiichi Fukuda, Takanori Kana, and Masaharu Kataoka

Seitai, a Kampo medicine, has an anti-inflammatory effect on ulcerative colitis, but cases have been reported of pulmonary arterial hypertension (PAH) as a side effect in patients with ulcerative colitis who took excessive amounts of it. In this paper, a collaborative research team from Cardiovascular Medicine and Gastroenterology confirmed the clinical reproducibility of findings suggestive of PAH, such as right ventricular hypertrophy and pulmonary vascular morphological abnormalities, in a rat model administered Seitai. Furthermore, since Seitai contains ligands for the Aryl hydrocarbon Receptor (AhR), the authors focused on the possibility that the AhR signal is involved in the development of PAH. They confirmed that in rats that developed PAH after being administered Seitai, the AhR signal was enhanced, and that the additional administration of an AhR antagonist alleviated the PAH. This study is highly valuable as a reverse translational research study based on clinically observed side effects. It not only elucidated the mechanism of the side effect but also identified the molecular mechanism of PAH development mediated by the AhR signal and proposed a new method for creating a PAH animal model using an AhR ligand.

(Keiichi Fukuda, Class of '62, Department of Internal Medicine, Cardiovascular Medicine)

Nature.

2020 Sep;585(7826):591-596. doi: 10.1038/s41586-020-2425-3

Toshiaki Teratani, Yohei Mikami, Nobuhiro Nakamoto, Takahiro Suzuki, Yosuke Harada, Koji Okabayashi, Yuya Hagihara, Nobuhito Taniki, Keita Kohno, Shinsuke Shibata, Kentaro Miyamoto, Harumichi Ishigame, Po-Sung Chu, Tomohisa Sujino, Wataru Suda, Masahira Hattori, Minoru Matsui, Takaharu Okada, Hideyuki Okano, Masayuki Inoue, Toshihiko Yada, Yuko Kitagawa, Akihiko Yoshimura, Mamoru Tanida, Makoto Tsuda, Yusaku Iwasaki, Takanori Kanai

The gut possesses mechanisms, including regulatory T cells (Treg cells), to suppress excessive host immune responses to external stimuli such as gut microbiota and diet. The breakdown of this intestinal immune regulatory mechanism is thought to cause inflammatory bowel disease (IBD). Previously, due to the comorbidity of IBD with conditions like depression and irritable bowel syndrome, the involvement of the autonomic nervous system in the development of IBD has been clinically assumed, but the detailed mechanism was not fully understood. This study revealed that antigen-presenting cells (APCs), which are crucial for the differentiation and maintenance of intestinal Treg cells, are located near nerves in the intestinal lamina propria. These APCs receive neural stimuli via muscarinic acetylcholine receptors (a type of neurotransmitter receptor) to differentiate and induce intestinal Treg cells. Furthermore, it was shown that when the left vagus nerve from the liver to the brainstem in mice was blocked, the amount of intestinal Treg cells significantly decreased, worsening the pathology of enteritis in the mouse model. This indicated that a "gut-liver-brain-gut vagal reflex" regulates the amount of intestinal Treg cells and maintains homeostasis. These findings are expected to lead to the elucidation of the pathogenic mechanisms of various diseases such as IBD, cancer, and gastrointestinal infections, and to the development of new therapeutic methods in the future.

(Yohei Mikami, Class of '85, Gastroenterology)

Biological Reviews.

2020 16 September; doi: 10.1111/brv.12645

Bouchekioua Y, Blaisdell AP, Kosaki Y, Tsutsui-Kimura I, Craddock P, Mimura M, Watanabe S.

Nat Rev Cancer.

2020 Sep 7. doi: 10.1038/s41568-020-0291-9.

Kenichiro Kinouchi & Paolo Sassone-Corsi