Endothelial TFEB signaling-mediated autophagic disturbance initiates microglial activation and cognitive dysfunction

Autophagy. 2023 Jun;19(6):1803-1820. doi: 10.1080/15548627.2022.2162244. Epub 2023 Jan 1.

Abstract

Cognitive impairment caused by systemic chemotherapy is a critical question that perplexes the effective implementation of clinical treatment, but related molecular events are poorly understood. Herein, we show that bortezomib exposure leads to microglia activation and cognitive impairment, this occurs along with decreased nuclear translocation of TFEB (transcription factor EB), which is linked to macroautophagy/autophagy disorder, STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL23A (interleukin 23 subunit alpha) expression. Pharmacological enhancement of TFEB nuclear translocation by digoxin restores lysosomal function and reduces STAT3-dependent endothelial IL23A secretion. As a consequence, we found that brain endothelial-specific ablation of Il23a ameliorated both microglia activation and cognitive dysfunction. Thus, the endothelial TFEB-STAT3-IL23A axis in the brain represents a critical cellular event for initiating bortezomib-mediated aberrant microglial activation and synapse engulfment. Our results suggest the reversal of TFEB nuclear translocation may provide a novel therapeutic approach to prevent symptoms of cognitive dysfunction during clinical use of bortezomib.Abbreviations: AAV: adeno-associated virus; BBB: blood-brain barrier; BTZ: bortezomib; DG: digoxin; DGs: dentate gyrus; DLG4/PSD95: discs large MAGUK scaffold protein 4; HBMECs: human brain microvascular endothelial cells; HP: hippocampus; IL23A: interleukin 23 subunit alpha; MBVECs: mouse brain vascular endothelial cells; mPFC: medial prefrontal cortex; NORT: novel object recognition test; OLT: object location test; PLX5622: 6-fluoro-N-([5-fluoro-2-methoxypyridin-3-yl]methyl)-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3- yl)methyl; PPP3/calcineurin: protein phosphatase 3; SBEs: STAT3 binding elements; shRNA: small hairpin RNA; SLC17A7/VGLUT1: solute carrier family 17 member 7; SLC32A1/VGAT: solute carrier family 32 member 1; STAT3: signal transducer and activator of transcription 3, TFEB: transcription factor EB; Ub: ubiquitin.

Keywords: Autophagy; IL23A; TFEB; cognitive dysfunction; digoxin; endothelial cells; microglia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy* / physiology
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Bortezomib / pharmacology
  • Cognitive Dysfunction* / metabolism
  • Endothelial Cells / metabolism
  • Humans
  • Interleukin-23
  • Lysosomes / metabolism
  • Mice
  • Microglia / metabolism
  • STAT3 Transcription Factor / metabolism

Substances

  • STAT3 Transcription Factor
  • Bortezomib
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Interleukin-23
  • TFEB protein, human

Grants and funding

This work was supported by the State Key Program of National Natural Science Foundations of China (grant no. 81930103 to F.H.), the National Key Research and Development Program of China (2022YFE0108600 to Y.M.L.), the National Natural Science Foundation of China (grant no. 81973300 to Y.M.L.; grant no. 82073946 to W.F.Y., grant no. 82104162 to X.X.L.; grant no. 81803506 to Q.J. and grant no. 82003764 to L.L.F.).