Membrane-enclosed extracellular vesicles, exosomes, are a critical part of intercellular communication in many biological systems. However, the regulation and biological implications of exosome excretion and uptake remain unclear. A recent study examined the role of cellular retinoic acid (RA) binding protein (Crabp1) in exosome secretion and its relationship to receptor interacting protein 140 (RIP140), a pro-inflammatory transcription co-regulator. Crabp1 knockout mice consistently showed deficits in negative control of exosome secretion and exhibited increased vulnerability to systemic inflammation. Crabp1 knockout mice had significantly elevated RIP140-containing exosomes in their blood and cerebrospinal fluid. Cell culture experiments suggested that exosome secretion can transfer RIP140 from neurons to macrophages, where it promotes macrophage inflammatory polarization. In vitro inhibition of the Crabp1 target mitogen-activated protein kinase (MAPK) blocked RIP140 exosome secretion, suggesting that Crabp1-regulated exosome secretion of RIP140 is mediated by the MAPK signaling pathway. Patient data showed Crabp1 expression is decreased in several human inflammatory diseases, which may indicate clinical relevance. This study is the first to suggest the regulation of exosome secretion via RA-Crabp1-MAPK signaling and that this mechanism can contribute to systemic inflammation by transporting RIP140 between cells.