The antioxidant enzyme Peroxiredoxin-1 controls stroke-associated microglia against acute ischemic stroke
Sinai Kim,
Wonhyo Lee,
Huiju Jo,
Seong-Keun Sonn,
Se-Jin Jeong,
Seungwoon Seo,
Joowon Suh,
Jing Jin,
Hyae Yon Kweon,
Tae Kyeong Kim,
Shin Hye Moon,
Sejin Jeon,
Jong Woo Kim,
Yu Ri Kim,
Eun-Woo Lee,
Hwa Kyoung Shin,
Sung Ho Park,
Goo Taeg Oh
Affiliations
Sinai Kim
Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
Wonhyo Lee
Department of Biological Sciences, Ulsan National Institute of Science & Technology (UNIST), Ulsan, South Korea
Huiju Jo
Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
Seong-Keun Sonn
Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
Se-Jin Jeong
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
Seungwoon Seo
Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
Joowon Suh
Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
Jing Jin
Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
Hyae Yon Kweon
Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
Tae Kyeong Kim
Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
Shin Hye Moon
Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
Sejin Jeon
Department of Biological Sciences and Biotechnology Major in Bio-Vaccine Engineering Andong National University, Andong, South Korea
Jong Woo Kim
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, South Korea; Department of Functional Genomics, University of Science and Technology (UST), Daejeon, South Korea
Yu Ri Kim
KM Convergence Research Division, Korea Institute of Oriental Medicine 1672, Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea
Eun-Woo Lee
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, South Korea; Department of Functional Genomics, University of Science and Technology (UST), Daejeon, South Korea
Hwa Kyoung Shin
Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea
Sung Ho Park
Department of Biological Sciences, Ulsan National Institute of Science & Technology (UNIST), Ulsan, South Korea; Corresponding author.
Goo Taeg Oh
Heart-Immune-Brain Network Research Center, Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea; Corresponding author.
Ischemic stroke is the leading cause of immortal disability and death worldwide. For treatment in the acute phase, it is necessary to control excessive reactive oxygen species (ROS) damage during ischemia/reperfusion (I/R). Microglia are well known to be closely associated with excessive ROS response in the early stage of I/R. However, the precise roles of microglia associated with mitigating ROS damage, and molecular markers of heterogenetic microglia in the I/R damaged brain has not been clarified. Here, we identified a new type of microglia associated with stroke in the I/R injured brain. Single-cell RNA sequencing (scRNA-seq) was used to assess transcriptional changes of microglia and immune cells in the contralateral (CL) and ipsilateral (IL) hemispheres after transient middle cerebral artery occlusion (tMCAO) surgery to mimic ischemic stroke. We classified a unique type of microglia with enhanced antioxidant function and markers similar to those of disease-associated microglia (DAM), designated them as stroke-associated microglia (SAM). The representative antioxidant enzyme, Peroxiredoxin-1 (Prdx1), was predominantly expressed in SAM and mediated ROS defense genes, including Txn1, Srx1, Mt1, and Mt2. In the Prdx1−/− I/R damaged brain, we observed significantly increased infarction, as assessed by TTC staining, and FACS analysis detected severe microglial cell death. Importantly, scRNA transcriptomics data showed that the SAM population was specifically decreased in Prdx1−/− mice and that these mice exhibited decreased ROS damage resistance. Inflammatory responses which were detected by ELISA and qPCR, were also increased in Prdx1−/− IL hemispheres. Finally, Prdx1-dependent antioxidative SAM were found to be essential for increasing the transcription levels of stroke-protective molecules, such as osteopontin and ferritin. A novel microglia type (SAM) is specifically activated in response to stroke I/R injury, and that Prdx1 expression is required for the activation and enhanced antioxidant function of SAM.
