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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number102347
JournalRedox Biology
Volume54
DOIs
StatePublished - Aug 2022

Keywords

  • Ischemic stroke
  • Peroxiredoxin-1 (Prdx1)
  • Reactive oxygen species (ROS)
  • Single cell RNA sequencing
  • Stroke-associated microglia (SAM)

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