1: Smad2 and Smad3 Inversely Regulate TGF-beta Autoinduction in Clostridium butyricum-Activated Dendritic Cells.

IMMUNITY

JUL 21 2015: 43 (1):65-79; 10.1016

Kashiwagi Ikkou, Morita Rimpei, Schichita Takashi, Komai Kyoko, Saeki Keita, Matsumoto Makoto, Takeda Kiyoshi, Nomura Masatoshi, Hayashi Atsushi, Kanai Takanori, Yoshimura Akihiko

The human gut is constantly inhabited by over 100 trillion intestinal bacteria, which are considered important for regulating immune balance and maintaining health. However, the molecular mechanisms by which intestinal bacteria regulate immune balance are not well understood. In this study, we focused on strains of the genus *Clostridium*, a probiotic known to improve bacterial flora in the digestive tract and suppress enteritis, and investigated the secretion of the anti-inflammatory cytokine transforming growth factor-β (TGF-β) and the induction mechanism of regulatory T cells (Tregs). As a result, we revealed that peptidoglycan, a major component of the cell membrane of *Clostridium* bacteria, acts on dendritic cells in the digestive tract to secrete TGF-β and induce Tregs. Peptidoglycan stimulates the receptor TLR2 to induce TGF-β via the ERK-AP1 pathway. Furthermore, we found that the transcription factors Smad2 and Smad3, which normally function downstream of TGF-β, are also involved in TGF-β production and Treg induction, and that they have completely opposite effects: Smad3 promotes this process, while Smad2 suppresses it. The elucidation of the molecular mechanism of TGF-β production and Treg induction raises expectations for the development of safe and effective preventive and therapeutic methods for inflammatory bowel disease using this bacterial strain.

(Akihiko Yoshimura, Department of Microbiology and Immunology, equivalent to the 60th graduating class; Ikkou Kashiwagi, 4th year, Doctoral Programs)

PNAS

SEP 8 2015: 112 (36):E4985-E4994; 10.1073

Kanatani Shigeaki, Honda Takao, Aramaki Michihiko, Hayashi Kanehiro, Kubo Ken-ichiro, Ishida Mami, Tanaka Daisuke H., Kawauchi Takeshi, Sekine Katsutoshi, Kusuzawa Sayaka, Kawasaki Takahiko, Hirata Tatsumi, Tabata Hidenori, Uhlen Per, Nakajima Kazunori

There are two types of nerve cells in the brain: excitatory neurons, which form the basic circuits, and inhibitory neurons, which regulate their activity. The brain functions correctly when these neurons are arranged in a balanced manner to form networks. An imbalance between excitation and inhibition has drawn attention for its potential association with conditions such as schizophrenia, autism, and epilepsy. In this study, we used the in utero electroporation technique we previously developed to introduce genes into the preoptic area of the fetal mouse brain and observed the movement of the inhibitory neurons born there. As a result, we found that they move caudally in bundles along a narrow route and enter the region that will become the future amygdala. We also discovered that along this migration path, some neurons change their direction of movement and head toward the cerebral cortex. Furthermore, we found that the selection of the destination for this cell migration is controlled by the ON/OFF switching of a specific molecular pathway. Specifically, we found that if the transcription factor COUP-TFII and the downstream receptor Neuropilin-2, whose expression it regulates, remain ON, the cells enter the amygdala. If this pathway is switched OFF midway, they change their direction of migration and move toward the cerebral cortex.

(Kazunori Nakajima, Department of Anatomy, 67th graduating class)

IMMUNITY

JUL 21 2015: 43 (1):175-186; 10.1016

Morita Hideaki, Arae Ken, Unno Hirotoshi, Miyauchi Kousuke, Toyama Sumika, Nambu Aya, Oboki Keisuke, Ohno Tatsukuni, Motomura Kenichiro, Matsuda Akira, Yamaguchi Sachiko, Narushima Seiko, Kajiwara Naoki, Iikura Motoyasu, Suto Hajime, McKenzie Andrew N. J., Takahashi Takao, Karasuyama Hajime, Okumura Ko, Azuma Miyuki, Moro Kazuyo, Akdis Cezmi A., Galli Stephen J., Koyasu Shigeo, Kubo Masato, Sudo Katsuko, Saito Hirohisa, Matsumoto Kenji, Nakae Susumu

MOLECULAR CELL

JUN 18 2015, 58 (6):1015-1027; 10.1016

Hisatsune Chihiro, Ebisui Etsuko, Usui Masaya, Ogawa Naoko, Suzuki Akio, Mataga Nobuko, Takahashi-Iwanaga Hiromi, Mikoshiba Katsuhiko