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bioRxiv · 10.1101/2024.07.08.602449

Detrimental Influence of Arginase-1 in Infiltrating Macrophages on Post-Stroke Functional Recovery and Inflammatory Milieu

Kim, H. S.·Jee, S. A.·Einisadr, A.·Seo, Y.·Seo, H. G.·Jang, B. S.·Park, H. H.·Chung, W.-S.·Kim, B. G.
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Abstract

Post-stroke inflammation critically influences functional outcomes following ischemic stroke. Arginase-1 (Arg1) is conventionally understood as 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 post-stroke recovery remains to be elucidated. This study investigates the functional impact of Arg1 expressed in macrophages on post-stroke recovery and inflammatory milieu. We observed a time-dependent increase in Arg1 expression, peaking at 7 days 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 FACS-sorted microglia revealed decreased TGF-{beta} signaling and pro-inflammatory cytokine activity in peri-infarct microglia from Arg1 cKO animals. In vitro co-culture experiments demonstrated that Arg1 activity in macrophages modulates microglial synaptic phagocytosis, providing evidence for macrophage-microglia interaction. These findings provide new insights into Arg1 function in CNS 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 therapeutic target for modulating post-stroke inflammation and improving functional recovery.

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Kim, H. S., Jee, S. A., Einisadr, A., Seo, Y., Seo, H. G., Jang, B. S., Park, H. H., Chung, W.-S., Kim, B. G.. 2024-07-11. Detrimental Influence of Arginase-1 in Infiltrating Macrophages on Post-Stroke Functional Recovery and Inflammatory Milieu. https://doi.org/10.1101/2024.07.08.602449

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