PARP14 inhibits microglial activation via LPAR5 to promote post-stroke functional recovery

Autophagy. 2021 Oct;17(10):2905-2922. doi: 10.1080/15548627.2020.1847799. Epub 2020 Dec 15.

Abstract

Stroke is a major public health problem leading to high rates of death and disability worldwide, but no effective pharmacological therapy is currently available except for the use of PLAT (plasminogen activator, tissue). Here we show that PARP14 (poly (ADP-ribose) polymerase family, member 14) level was significantly increased in the peri-infarct zone of photothrombotic stroke (PT) mice. Genetic knockdown and pharmacological inhibition of PARP14 aggravated functional impairment and increased infarct volume in PT mice, while overexpression of PARP14 displayed the opposite effects. Furthermore, PARP14 was abundant in microglia, and downregulation of PARP14 increased post-stroke microglial activation, whereas overexpression of PARP14 alleviated microglial activation, possibly through microglial macroautophagy/autophagy modulation. Mechanistically, overexpression of PARP14 suppressed Lpar5 (lysophosphatidic acid receptor 5) gene transcription to inhibit microglial activation post stroke. Taken together, PARP14 is a stroke-induced signal that restricts microglial activation and promotes functional recovery, and can serve as a novel target to develop new therapeutic agents for stroke. Moreover, these findings may be conducive to proper use of various PARP inhibitors.Abbreviations: 3-MA: 3-methyladenine; AIF1/Iba-1: allograft inflammatory factor 1; CNS: central nervous system; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; ELISA: enzyme-linked immunosorbent assay; FBS: fetal bovine serum; GFAP: glial fibrillary acidic protein; IL1B/IL-1β: interleukin 1 beta; IL6/IL-6: interleukin 6; LPAR5: lysophosphatidic acid receptor 5; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; NOS2/iNOS: nitric oxide synthase 2, inducible; OGD: oxygen glucose deprivation; PAR: polymer of poly (ADP ribose); PARP: poly (ADP-ribose) polymerase family; PBS: phosphate-buffered saline; PLAT/tPA: plasminogen activator, tissue; PT: photothrombotic stroke; qPCR: quantitative polymerase chain reaction; Rap: rapamycin; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SQSTM1: sequestosome 1; TNF/TNF-α: tumor necrosis factor.

Keywords: Autophagy; functional recovery; ischemic stroke; lysophosphatidic acid receptor 5; microglial activation; poly (ADP-ribose) polymerase 14.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins* / metabolism
  • Down-Regulation
  • Mice
  • Microglia / metabolism
  • Poly(ADP-ribose) Polymerases / genetics
  • RNA-Binding Proteins / metabolism
  • Stroke* / genetics

Substances

  • Caenorhabditis elegans Proteins
  • FOX-1 protein, C elegans
  • RNA-Binding Proteins
  • Parp14 protein, mouse
  • Poly(ADP-ribose) Polymerases

Grants and funding

This work was supported by grants from National Key Research and Development Program of China (2017YFA0104303), China Postdoctoral Science Foundation funded project (2019M661700), Jiangsu Planned Projects for Postdoctoral Research Funds (2019K160), the Natural Science Foundation of Jiangsu Province (BK20170593), National Natural Science Foundation of China (82003735, 81673410, 81761138048, 81973304, 81903591), National Science and Technology Major Project (2020 ZX09201015), Jiangsu Innovation & Entrepreneurship Team Program, CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-004), and the Fundamental Research Funds for the Central Universities (2242020K40128, 2242019R20013).