Regulation of exosome secretion by cellular retinoic acid binding protein 1 contributes to systemic anti-inflammation

Yi Wei Lin, Jennifer Nhieu, Chin Wen Wei, Yu Lung Lin, Hiroyuki Kagechika, Li Na Wei

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Intercellular communications are important for maintaining normal physiological processes. An important intercellular communication is mediated by the exchange of membrane-enclosed extracellular vesicles. Among various vesicles, exosomes can be detected in a wide variety of biological systems, but the regulation and biological implication of exosome secretion/uptake remains largely unclear.

METHODS: Cellular retinoic acid (RA) binding protein 1 (Crabp1) knockout (CKO) mice were used for in vivo studies. Extracellular exosomes were monitored in CKO mice and relevant cell cultures including embryonic stem cell (CJ7), macrophage (Raw 264.7) and hippocampal cell (HT22) using Western blot and flow cytometry. Receptor Interacting Protein 140 (RIP140) was depleted by Crispr/Cas9-mediated gene editing. Anti-inflammatory maker was analyzed using qRT-PCR. Clinical relevance was accessed by mining multiple clinical datasets.

RESULTS: This study uncovers Crabp1 as a negative regulator of exosome secretion from neurons. Specifically, RIP140, a pro-inflammatory regulator, can be transferred from neurons, via Crabp1-regulated exosome secretion, into macrophages to promote their inflammatory polarization. Consistently, CKO mice, defected in the negative control of exosome secretion, have significantly elevated RIP140-containing exosomes in their blood and cerebrospinal fluid, and exhibit an increased vulnerability to systemic inflammation. Clinical relevance of this pathway is supported by patients' data of multiple inflammatory diseases. Further, the action of Crabp1 in regulating exosome secretion involves its ligand and is mediated by its downstream target, the MAPK signaling pathway.

CONCLUSIONS: This study presents the first evidence for the regulation of exosome secretion, which mediates intercellular communication, by RA-Crabp1 signaling. This novel mechanism can contribute to the control of systemic inflammation by transferring an inflammatory regulator, RIP140, between cells. This represents a new mechanism of vitamin A action that can modulate the homeostasis of system-wide innate immunity without involving gene regulation. Video Abstract.

Original languageEnglish (US)
Article number69
JournalCell Communication and Signaling
Volume19
Issue number1
DOIs
StatePublished - Jun 30 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Crabp1
  • Exosome
  • Inflammation
  • Macrophage
  • Neuron
  • RIP140
  • Retinoic acid

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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