Detrimental influence of Arginase-1 in infiltrating macrophages on poststroke functional recovery and inflammatory milieu

• 成果类型: Article
• 署名作者: Kim, Hyung Soon; Jee, Seung Ah; Einisadr, Ariandokht; Seo, Yeojin; Seo, Hyo Gyeong; Jang, Byeong Seong; Park, Hee Hwan; Chung, Won-Suk; Kim, Byung Gon
• 署名单位: Ajou University; Ajou University; Korea Advanced Institute of Science & Technology (KAIST); Institute for Basic Science - Korea (IBS); Ajou University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11287
• DOI: 10.1073/pnas.2413484122
• 发表日期: 2025-02-18
• 关键词: ischemic-stroke; spinal-cord; endovascular therapy; fibrotic scar; microglia; synapse; cells; regeneration; thrombectomy; leukocytes

摘要

Poststroke inflammation critically influences functional outcomes following ischemic stroke. Arginase- 1 (Arg1) is considered a marker for anti- inflammatory macrophages, associated with the resolution of inflammation and promotion of tissue repair in various pathological conditions. However, its specific role in poststroke recovery remains to be elucidated. This study investigates the functional impact of Arg1 expressed in macrophages on poststroke recovery and inflammatory milieu. We observed a time- dependent increase in Arg1 expression, peaking at 7 d after photothrombotic stroke in mice. Cellular mapping analysis revealed that Arg1 was predominantly expressed in LysM- positive infiltrating macrophages. Using a conditional knockout (cKO) mouse model, we examined the role of Arg1 expressed in infiltrating macrophages. Contrary to its presumed beneficial effects, Arg1 cKO in LysM- positive macrophages significantly improved skilled forelimb motor function recovery after stroke. Mechanistically, Arg1 cKO attenuated fibrotic scar forma-tion, enhanced peri- infarct remyelination, and increased synaptic density while reduc-ing microglial synaptic elimination in the peri- infarct cortex. Gene expression analysis of fluorescence- activated single cell sorting (FACS)- sorted CD45low microglia revealed decreased transforming growth factor- beta (TGF- beta) signaling and proinflammatory cytokine activity in peri- infarct microglia from Arg1 cKO animals. In vitro coculture experiments demonstrated that Arg1 activity in macrophages modulates microglial synaptic phagocy-tosis, providing evidence for macrophage-microglia interaction. These findings present unique insights into the function of Arg1 in central nervous system injury and highlight an interaction between infiltrating macrophages and resident microglia in shaping the post-stroke inflammatory milieu. Our study identifies Arg1 in macrophages as a potential ther-apeutic target for modulating poststroke inflammation and improving functional recovery.