1: Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury

Nat Med.

2018 Feb;24(2):232-238. doi: 10.1038/nm.4462. Epub 2018 Jan 8.

Koshu Okubo, Miho Kurosawa, Mako Kamiya, Yasuteru Urano, Akari Suzuki, Kazuhiko Yamamoto, Koji Hase, Koichiro Homma, Junichi Sasaki, Hiroaki Miyauchi, Tatsuo Hoshino, Matsuhiko Hayashi, Tanya N Mayadas & Junichi Hirahashi

In disasters, trauma is common among victims. Among these cases, rhabdomyolysis, a condition where muscles are destroyed by mechanical compression, often causes acute kidney dysfunction, leading to life-threatening crush syndrome. However, the detailed mechanism of why muscle breakdown causes kidney damage was not clear. Furthermore, treatment options for this condition are limited to specialized treatments that must be administered at medical institutions, such as massive fluid resuscitation and renal replacement therapy, and there are currently no rapid, simple, portable, and administrable methods for preventing acute kidney injury (AKI) at disaster sites. In this study, the research group discovered that the activation of platelets upon recognizing muscle-derived heme, which in turn induces macrophage extracellular trap (METs) formation—a phenomenon of extracellular chromatin release by macrophages (a type of white blood cell)—is a key factor in the development of acute kidney injury secondary to rhabdomyolysis. The research group also found that lactoferrin, a multifunctional protein in the body, can prevent this pathological condition, suggesting its potential to significantly contribute to disaster medicine. This report is the world's first to show that METs are involved in the pathology of a disease, and it was published in *Nature Medicine* in February 2018.

(Junichi Hirahashi, Department of General Medicine, 72nd Graduating Class)

NATURE COMMUNICATIONS,

9 10.1038/s41467-018-05044-4 JUL 16 2018

Tasaki Shinya, Suzuki Katsuya, Kassai Yoshiaki, Takeshita Masaru, Murota Atsuko, Kondo Yasushi, Ando Tatsuya, Nakayama Yusuke, Okuzono Yuumi, Takiguchi Maiko, Kurisu Rina, Miyazaki Takahiro, Yoshimoto Keiko, Yasuoka Hidekata, Yamaoka Kunihiro, Morita Rimpei, Yoshimura Akihiko, Toyoshiba Hiroyoshi, Takeuchi Tsutomu

For rheumatoid arthritis (RA), advances in disease-modifying antirheumatic drugs have made it possible to suppress disease progression. However, symptoms such as pain, functional impairment, and fatigue can persist, and a state of sustained, drug-free remission has not yet been sufficiently achieved. Therefore, we administered drug therapy to patients with clinically observable inflammation and investigated the characteristics of their molecular state when they reached a state of remission with almost no joint pain or swelling (clinical remission). Based on data on the expression levels of molecules in patients' peripheral blood, we defined molecular remission. By observing the molecular state over time, it became clear that drug therapy induces molecular remission and that the degree of this remission is crucial for achieving sustained remission. [Figure] On the other hand, we also found that some molecular characteristics still differed from those of healthy individuals even after drug therapy, and that these are characteristics of RA patients not associated with the currently used indicators for inflammation levels or physical disability. Furthermore, an analysis using public data on molecular information within patients revealed commonalities with the characteristics of patients with inflammatory bowel disease and obesity, suggesting potential applications for elucidating the pathology of these diseases and for drug discovery. We intend to advance our research toward the realization of precision medicine for RA and new drug discovery.

(Tsutomu Takeuchi (59th Graduating Class) and Katsuya Suzuki (75th Graduating Class), Department of Rheumatology and Collagen Disease)

CURRENT OPINION IN NEUROBIOLOGY,

50 1-6; 10.1016/j.conb.2017.10.016 JUN 2018

Okano Hideyuki, Kishi Noriyuki