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

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

doi:10.1186/s12964-021-00751-w

Abstract

BackgroundIntercellular 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.MethodsCellular 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.ResultsThis 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.ConclusionsThis 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.EB6KXQYbkzhu3R444VcR3RVideo

Highlights

Intercellular communications are important for maintaining normal physiological processes
We present data showing the regulation of intercellular, neuron-macrophage, and communication via exosomes by retinoic acid (RA)-Crabp1, which represents a novel mechanism of vitamin A action that rapidly modulates system-wide propagation of specific signals to maintain homeostasis
Careful studies comparing Crabp1 knockout (CKO) and wild type (WT) mice revealed that the plasma Receptor Interacting Protein 140 (RIP140) level was higher in CKO mice as compared to wild type mice (Fig. 1a)

Summary

Introduction

Intercellular communications are important for maintaining normal physiological processes. Intercellular communications via secreting and receiving signals are important for maintaining normal physiological processes [1, 2]. Exosomes are increasingly recognized in a wide range of biological systems; but specific physiological or pathological stimuli or regulatory pathways for exosome secretion/action remain poorly understood. Exosomes range from 30 to 100 nm in diameter, and are generated from endosome-originated multivesicular bodies (MVBs) [4]. They are released mainly through the fusion of MVBs with plasma membrane. This study reports an example of intercellular communication initiated from neuron, via secreting exosomes, to modulate microglia/macrophage functions

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