International Medical News

No.520ISSN 0535-1405

INTERNATIONAL MEDICAL NEWSInternational Medical Society of Japan
Since 1925
November 30, 2023
Published by International Medical Society of Japan,Chairman,Board of Directors:Kenichi Ishibashi, MD, PhD
Editors: K. Ito, MD, PhD, T. Kondo, MD,K. Ichihashi, MD, PhD, T.Murakami, PhD,R.Nagai, MD, PhD,T. Sumiyama, MD, PhD, I.Taniguchi, MD, PhD,andT.Yamazaki, MD,PhD

1-11-9-3F Kamiuma,Setagaya-ku,
Tokyo154-0011,Japan.
TEL03(5486)0601 FAX03(5486)0599 E-mail:imsj@imsj.or.jp https://www.imsj.or.jp/The 461th International Symposium on Therapy
The 461th International Symposium on Therapy was held at the Kioi forum in Tokyo on
September 21, 2023. Dr. Ryozo Nagai, Director of the International Medical Society ofJapan (IMSJ), presided over the meeting.

Inflammation and disease
Introductory Message from the Chair
Ryozo Nagai, MD, PhD
Director, IMSJInternational Medical News

【Discourse】
Diversification of pharmaceuticals and future prospects
Tsuji Masahiro
Fellow
Center for Research and Development Strategy,
Japan Science and Technology Agency

LectureⅠ
Chronic inflammation in multimorbidity
Ichiro Manabe MD, PhD
Professor
Department of Systems Medicine,
Graduate School of Medicine, Chiba University
With the aging of the population, the number of patients with multimorbidity, who sufferfrom a variety of chronic noncommunicable diseases, especially cardiovascular diseases,
is rapidly increasing. There are interplays between comorbidities; for example, heart
failure and chronic kidney disease interact with one another (cardiorenal syndrome). It istherefore important to understand how multimorbidity develops through the interactions
between diseases. In my talk I will focus on macrophages and show how macrophages
contribute to organ crosstalk and chronic inflammation.

International Medical News

LectureⅡ
Sterile inflammation and inflammasomes
Masafumi Takahashi, MD, PhD
Professor
Division of Inflammation ResearchCenter for Molecular Medicine
Jichi Medical University

Inflammation plays a pivotal role in the pathogenesis of cardiovascular andlifestyle-related diseases, including atherosclerosis and myocardial infarction.
Inflammation is a biological process in which inflammatory and immune cells, suchas macrophages and neutrophils, respond to infection or harmful substances todefend the body and eliminate pathogens and harmful substances. However,pathogens and harmful substances are not directly involved in cardiovascular andlifestyle-related diseases, and it has been unclear how such inflammation istriggered. Such inflammation in the absence of infection is referred to as sterile
inflammation. Recent evidence indicates that intracellular molecular complexes
called inflammasomes play an important role as one of the triggering mechanismsof sterile inflammation.
The inflammasomes generally consist of three components: a pattern-recognition
receptor (PRR) as a sensor, ASC as an adaptor, and inflammatory caspases as aneffector. To date, there have been reported several types of inflammasomes. Of
these, the NLRP3 inflammasome, formed by the sensor NLRP3, is primarily implicatedin the pathogenesis of sterile inflammatory diseases. When stimulated by danger
signals, such as ATP released from dead cells or uric acid crystals that cause gout
attacks, NLRP3 is activated and forms NLRP3 inflammasome complex, resulting in
the activation of caspase-1 (Casp1). Since Casp1 is originally identified as an IL-1βconverting enzyme (ICE), activated Casp1 processes the pro-IL-1β to the active(mature) IL-1β, a potent inflammatory cytokine. Activated Casp1 also processes a
pore-forming molecule GSDMD to form pores on the plasma membrane, releasing
active IL-1β to the outside of the cells and triggering inflammation. On the otherhand, the influx of water into the cells through these pores causes lytic cell death
due to cell swelling and rupture. This type of inflammatory cell death is known aspyroptosis. The concept of inflammasome was discovered and proposed in 2002,

International Medical Newsand in 2006, it was revealed that NLRP3 inflammasome mediates inflammation ingout attacks; therefore, NLRP3 inflammasome has attracted much attention as a
new molecular mechanism that induces sterile inflammation.
Dysregulation of the NLRP3 inflammasome has been implicated in various diseases
including cryopyrin periodic fever syndrome (CAPS), cardiovascular disease, kidneydisease, metabolic diseases, and cancer. Among them, CAPS is a rareautoinflammatory syndrome caused by a gain-of-function mutation of NLRP3,
which is characterized by cold-induced fever and inflammation. We recently foundthat CAPS-associated NLRP3 mutants form cryo-sensitive aggregates that function
as a scaffold for inflammasome assembly and reported a novel mechanism of
NLRP3 inflammasome activation. We have also reported that excessive IL-1β
production via NLRP3 inflammasome activation occurs in cardiovascular diseases
such as atherosclerosis, aortic aneurysm, myocardial infarction, Kawasaki disease,and septic cardiomyopathy, and that inhibition of NLRP3 inflammasome lead to
improvement of these diseases. Furthermore, we have reported novel danger
signals to activate NLRP3 inflammasome and regulatory mechanisms of NLRP3
inflammasome activation.
At present, there are no direct inhibitors targeting the NLRP3 inflammasome
available for clinical application. Instead, IL-1β-targeting agents have been used.
Among these, canakinumab, a fully humanized monoclonal IL-1β antibody, hasbeen approved for CAPS in Japan since 2011 and has shown significant efficacy. In
addition, in 2017, a large clinical trial (CANTOS) demonstrated that canakinumab
significantly improved inflammatory status and reduced recurrent cardiovascular
events in patients with previous myocardial infarction who had residual
inflammatory risk. Furthermore, the use of colchicine, which can inhibit the NLRP3
inflammasome formation, reduced the occurrence of cardiovascular events inpatients with recent myocardial infarction or chronic coronary artery disease(COLCOT [2019] and LoDoCo2 [2020] trials). These findings suggest that the NLRP3
inflammasome is a novel therapeutic target for sterile inflammatory diseases.