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 (LPS) 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 LPS-stimulated cells were sufficient to cause NF-kappaB activation in naïve cells, indicating functionality in recipient cells. A single injection of exosomes attenuated thermal hyperalgesia in a mouse model of inflammatory pain, suggesting an immunoprotective role for macrophage-derived exosomes. We also show that circulating miRNAs altered in patients with complex regional pain syndrome are trafficked by exosomes. Macrophage-derived exosomes carry a protective signature that is altered when secreting cells are exposed to an inflammatory stimulus. 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.

Macrophage-secreted Exosomes Delivering miRNA-21 Inhibitor can Regulate BGC-823 Cell Proliferation

“…Exosome secretion of microvesicles transporting miRNAs, mRNAs, and proteins through bodily fluids facilitates intercellular communication and can elicit an immune response (McDonald et al, 2014).…”

Circulating microRNA Signatures in Rodent Models of Pain

“…Exosome-bound Wnts and their signaling activities have been functionally implicated in the development of Drosophila and in fibroblastpromoted cancer metastasis [70]. Our previous investigation of exosomes derived from mouse macrophage cells stimulated with lipopolysaccharides showed elevated levels of cytokines and miRNAs that mediate inflammation; sequencing of exosomal transcriptome revealed the presence of several transcripts belonging to the Wnt signaling pathway [71]. Not all the miRNAs and mRNAs present in a cell are packaged into the exosomes and the molecular mechanisms determining this sorting are not well understood.…”

MicroRNA Biology and Pain

“…Although exosomes derived from both unstimulated and LPS-stimulated cells reduced CFA-induced thermal hyperalgesia, those from stimulated cells also attenuated paw swelling and showed an analgesic response at earlier time points after delivery. 133 The absence of pain and swelling in saline-treated paws after exosome injection demonstrates that exosomal delivery does not induce a hypersensitivity response. This combined with the fact that exosomes can be loaded with nucleic acids or drugs suggests a potential role for exosomes in pain therapy.…”