A research group led by Professor Takashi Yahata of the Basic Medical Sciences, Tokai University School of Medicine, in collaboration with Professor Toshio Miyata of the Tohoku University Graduate School of Medicine and others, has clarified a new mechanism by which inflammation is prolonged. The findings were published in the online edition of Cell Death Discovery.
Provided by Tokai University
The research group induced temporary injury to the skeletal muscle of mice and investigated how PAI-1 functions at the site of inflammation. As a result, they confirmed that PAI-1 expression was significantly increased in the damaged muscle tissue. In particular, CCR2+Ly6C+ inflammatory macrophages that gather at the inflammatory site were found to produce large amounts of PAI-1.
Next, when examining mice lacking PAI-1, they confirmed that inflammation was attenuated and the regeneration of damaged muscle progressed faster compared to normal mice. The expression of pro-inflammatory cytokines decreased, while the expression of IL-10, which acts to suppress inflammation, increased. This demonstrated that PAI-1 is a factor that prolongs inflammation and hinders tissue regeneration.
Furthermore, suppression of inflammation and promotion of muscle tissue regeneration were also observed in mice engineered so that PAI-1 could not be produced solely by inflammatory macrophages. This result revealed that the primary factor prolonging inflammation is not PAI-1 in the blood, but rather the PAI-1 produced locally by macrophages at the inflammatory site.
The core discovery of this study lies in clarifying the mechanism by which PAI-1 directly hinders macrophages "ability to clear away dead cells." Normally, dead cells display an "eat me" signal called CRT on their surface. Macrophages recognize CRT through a receptor on their own surface called LRP-1, taking in and processing the dead cells, a process known as efferocytosis.
However, it was discovered that PAI-1 binds to LRP-1 more strongly than CRT does, competitively hindering the recognition of CRT. In other words, even when dead cells present the "please eat me" sign, PAI-1 blocks the receptor first, making it impossible for macrophages to clear the dead cells effectively. Consequently, the dead cells remain at the inflammatory site, prolonging inflammation and delaying tissue repair.
Additionally, in mice administered the PAI-1 inhibitor TM5614, the dead-cell removal function of macrophages improved, which promoted the resolution of inflammation and muscle tissue regeneration. This indicates that therapies targeting PAI-1 could potentially be effective against inflammatory diseases and tissue repair disorders.
This study clarified the inhibition of macrophage efferocytosis as a new mechanism by which PAI-1 exacerbates inflammation. While PAI-1 has previously been known as a factor involved in blood coagulation and fibrosis, this research shows that it is a critical factor that regulates immune cell function directly at the site of inflammation and participates in prolonging the inflammatory response.
Although this study is basic research using a skeletal muscle injury model, macrophages are deeply involved in many inflammatory diseases. Therefore, the inhibition of efferocytosis by macrophage-derived PAI-1 may be a common mechanism shared across various diseases accompanied by chronic inflammation, such as arthritis, colitis, arteriosclerosis, and cancer. Furthermore, because the PAI-1 inhibitor TM5614 can be administered orally, it holds promise as a new anti-inflammatory drug candidate with a mechanism of action distinct from conventional steroids and cytokine inhibitors.
Moving forward, verification of its efficacy and safety in human inflammatory diseases is expected to lead to the development of new treatments for chronic inflammation and tissue repair disorders.
Journal Information
Publication: Cell Death Discovery
Title: Inflammatory macrophage-derived plasminogen activator inhibitor-1 exacerbates inflammation through efferocytosis inhibition
DOI: 10.1038/s41420-026-03076-0
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.