title: Functional significance of macrophage-derived exosomes in inflammation and pain.
abstract: Exosomes, secreted microvesicles transporting microRNAs (miRNAs), mRNAs, and proteins through bodily fluids, facilitate intercellular communication and elicit immune responses. Exosomal contents vary, depending on the source and the physiological conditions of cells, and can provide insights into how cells and systems cope with physiological perturbations. Previous analysis of circulating miRNAs in patients with complex regional pain syndrome (CRPS), a debilitating chronic pain disorder, revealed a subset of miRNAs in whole blood that are altered in the disease. To determine functional consequences of alterations in exosomal biomolecules in inflammation and pain, we investigated exosome-mediated information transfer in vitro, in a rodent model of inflammatory pain, and in exosomes from patients with CRPS. Mouse macrophage cells stimulated with lipopolysaccharides secrete exosomes containing elevated levels of cytokines and miRNAs that mediate inflammation. Transcriptome sequencing of exosomal RNA revealed global alterations in both innate and adaptive immune pathways. Exosomes from lipopolysaccharide-stimulated cells were sufficient to cause nuclear factor-κB activation in naive cells, indicating functionality in recipient cells. A single injection of exosomes attenuated thermal hyperalgesia in a murine model of inflammatory pain, suggesting an immunoprotective role for macrophage-derived exosomes. Macrophage-derived exosomes carry a protective signature that is altered when secreting cells are exposed to an inflammatory stimulus. We also show that circulating miRNAs altered in patients with complex regional pain syndrome are trafficked by exosomes. With their systemic signaling capabilities, exosomes can induce pleiotropic effects potentially mediating the multifactorial pathology underlying chronic pain, and should be explored for their therapeutic utility.
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, PA, USA School of Biomedical Engineering, Science & Health Systems, Drexel University, Philadelphia, PA, USA Department of Neurology, Drexel University College of Medicine, Philadelphia, PA, USA Department of Cancer Biology, Thomas Jefferson University, Cancer Genomics Laboratory, Kimmel Cancer Center, Philadelphia, PA, USA Janssen Research and Development LLC, Spring House, PA, USA Department of Molecular Medicine, Sapienza Universita di Roma, Rome, Italy.
authors.forename: Marguerite K
authors.initials: MK
authors.lastname: McDonald
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Tian
authors.forename: Rehman A
authors.initials: RA
authors.lastname: Qureshi
authors.forename: Michael
authors.initials: M
authors.lastname: Gormley
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Ruby
authors.initials: R
authors.lastname: Gao
authors.forename: Enrique
authors.initials: E
authors.lastname: Aradillas Lopez
authors.forename: Guillermo M
authors.initials: GM
authors.lastname: Alexander
authors.forename: Ahmet
authors.initials: A
authors.lastname: Sacan
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.forename: Seena K
authors.initials: SK
authors.lastname: Ajit
mesh_terms: D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D016207:Cytokines; D035683:MicroRNAs; D016328:NF-kappa B
keywords: CRPS; Exosome; Inflammation; NF-kappaB; Pain; Toll-like receptors; miRNA