Neutrophil Nanovesicle Protects against Experimental Autoimmune Encephalomyelitis through Enhancing Myelin Clearance by Microglia

Shishi Shen, Xi Cheng, Luyao Zhou, Yipeng Zhao, Hai Wang, Jie Zhang, Xiaobo Sun, Yuge Wang, Yaqing Shu, Yanteng Xu, Yu Tao, Mingqiang Li, Zhengqi Lu, Wei Cai, Guangjun Nie, Wei Qiu

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Timely clearance of myelin debris is the premise of neuroinflammation termination and tissue regeneration in multiple sclerosis (MS). Microglia are the main scavengers of myelin debris in MS lesions, but its phagocytic capability is limited in MS patients. Here, we develop neutrophil-derived nanovesicles (NNVs) to enhance the efficiency of myelin debris clearance in microglia for MS therapy. RNA sequencing (RNAseq) results demonstrate that NNVs treatment ameliorates lesional neuroinflammation of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Consequently, EAE mice exhibit favorable neurological functions and white matter integrity after NNVs treatment. Specifically, NNVs treatment upregulates the expression of nuclear factor E2-related factor 2 (NRF2) in microglia, as revealed by Assay for Transposase Accessible Chromatin using sequencing (ATACseq). We also demonstrate that NRF2 can activate the transcription of RUBCN (RUN domain and cysteine-rich domain containing Beclin 1-interacting protein), which in turn enhances LC3-associated phagocytosis (LAP) in microglia. As a result, myelin debris engulfed by microglia can be efficiently catabolized in NNVs-treated EAE mice without obvious side effects. Together, this study proves that NNVs can modulate neuroinflammation by clearing myelin debris and is a promising MS treatment strategy.

Original languageEnglish (US)
Pages (from-to)18886-18897
Number of pages12
JournalACS Nano
Volume16
Issue number11
DOIs
StatePublished - Nov 22 2022

Keywords

  • experimental autoimmune encephalomyelitis
  • microglia
  • multiple sclerosis
  • myelin
  • neutrophil nanovesicles

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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