1: MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1

NATURE MEDICINE

23 (6):723-+; 10.1038/nm.4312 JUN 2017

Shichita Takashi, Ito Minako, Morita Rimpei, Komai Kyoko, Noguchi Yoshiko, Ooboshi Hiroaki, Koshida Ryusuke, Takahashi Satoru, Kodama Tatsuhiko, Yoshimura Akihiko

Cerebral infarction accounts for about 70% of strokes, and the total number of patients is said to exceed one million, but effective treatments are scarce. We have previously reported that macrophages infiltrate the site of cerebral infarction, exacerbating inflammation and worsening neurological symptoms. Macrophages that have infiltrated the infarcted area recognize components derived from dead cells called DAMPs and release inflammatory cytokines. However, three to four days after onset, DAMPs disappear and the inflammation begins to resolve. In this study, we identified the scavenger receptor as the receptor that processes DAMPs in macrophages and further found that the transcription factor Mafb induces the expression of this receptor. We also discovered that the vitamin A derivative Am80, used in the treatment of leukemia, activates Mafb, accelerates the clearance of DAMPs, reduces the size of the cerebral infarction area, and hastens the recovery of neurological symptoms. This study not only elucidates the mechanism of inflammation resolution after brain injury but also presents a completely new therapeutic strategy to accelerate it.

(Akihiko Yoshimura, Department of Microbiology and Immunology, '60 equivalent)

NATURE COMMUNICATIONS

8 10.1038/ncomms15338 MAY 22 2017

Kondo Taisuke, Morita Rimpei, Okuzono Yuumi, Nakatsukasa Hiroko, Sekiya Takashi, Chikuma Shunsuke, Shichita Takashi, Kanamori Mitsuhiro, Kubo Masato, Koga Keiko, Miyazaki Takahiro, Kassai Yoshiaki, Yoshimura Akihiko

With immune checkpoint inhibitors becoming part of standard treatment, cancer immunotherapy has entered a new era. Adoptive immunotherapy, in which cytotoxic T cells that have accumulated in tumors are expanded ex vivo and returned to the patient, is also being actively researched. However, the T cells gathered in the tumor are already in an exhausted state, making them difficult to proliferate. Therefore, if these exhausted T cells could be rejuvenated and reactivated, a strong anti-tumor effect could be achieved. We found that when T cells that were once activated and then became exhausted are co-cultured with stromal cells expressing the signal molecule Notch, rejuvenated, naive-like cells emerge. These T cells responded to antigens and proliferated more rapidly than any other type of T cell, had a longer lifespan, and exhibited strong anti-tumor activity. Although the mechanism is not yet understood, this study is expected to have a major impact on future anti-tumor immunotherapy as it has shown that it is possible to rejuvenate exhausted T cells through the simple method of co-culturing them with stromal cells.

(Akihiko Yoshimura, Department of Microbiology and Immunology, '60 equivalent)