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Proc. Natl. Acad. Sci. USA, Feb 18 2025, 122 (7) | https://doi.org/10.1073/pnas.2413484122 Detrimental influence of Arginase-1 in infiltrating macrophages on poststroke functional recovery and inflammatory milieu

Hyung Soon Kim^{1 2}, Seung Ah Jee ^{1 2}, Ariandokht Einisadr ^{1 2}, Yeojin Seo ^{1 2}, Hyo Gyeong Seo ^{1 2}, Byeong Seong Jang ^{1 2}, Hee Hwan Park ^{1 2}, Won-Suk Chung ^{3 4}, Byung Gon Kim ^{1 2 5 *}

¹Department of Brain Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
²Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Republic of Korea.
³Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
⁴Center for Vascular Biology, Institute for Basic Science, Daejeon 34126, Republic of Korea.
⁵Department of Neurology, Ajou University School of Medicine, Suwon 16499, Republic of Korea.

^*Corresponding author: correspondence to Byung Gon Kim

Abstract

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 formation, enhanced peri-infarct remyelination, and increased synaptic density while reducing microglial synaptic elimination in the peri-infarct cortex. Gene expression analysis of fluorescence-activated single cell sorting (FACS)-sorted CD45^low microglia revealed decreased transforming growth factor-β (TGF-β) 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 phagocytosis, 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 poststroke inflammatory milieu. Our study identifies Arg1 in macrophages as a potential therapeutic target for modulating poststroke inflammation and improving functional recovery.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-18)
연구진국내 연구진
분야 생명과학 > 신경생물학

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