Sarcoidosis exosomes stimulate monocytes to produce pro-inflammatory cytokines and CCL2

Abstract

Pulmonary sarcoidosis has unknown etiology, a difficult diagnostic procedure and no curative treatment. Extracellular vesicles including exosomes are nano-sized entities released from all cell types. Previous studies of exosomes from bronchoalveolar lavage fluid (BALF) of sarcoidosis patients have revealed pro-inflammatory components and abilities, but cell sources and mechanisms have not been identified. In the current study, we found that BALF exosomes from sarcoidosis patients, but not from healthy individuals, induced a dose-dependent elevation of intracellular IL-1β in monocytes. Analyses of supernatants showed that patient exosomes also induced release of IL-1β, IL-6 and TNF from both PBMCs and enriched monocytes, suggesting that the observed effect is direct on monocytes. The potently chemotactic chemokine CCL2 was induced by exosomes from a subgroup of patients, and in a blocking assay the exosome-induced CCL2 was reduced for 13 out of 19 patients by the asthma drug Montelukast, a cysteinyl leukotriene receptor antagonist. Further, reactive oxygen species generation by PBMCs was induced to a higher degree by patient exosomes compared to healthy exosomes. These findings add to an emerging picture of exosomes as mediators and disseminators of inflammation, and open for further investigations of the link between CCL2 and exosomal leukotrienes in sarcoidosis.

MiR-154-5p-MCP1 Axis Regulates Allergic Inflammation by Mediating Cellular Interactions

“…A previous study has shown that exosomes contribute to the pathogenesis of asthma (11). Additionally, exosomes from the broncho alveolar lavage fluid (BALF) of sarcoidosis patients can induce the expression of CCL2 (MCP1) (41). Here, we showed that exosomes from antigen-stimulated RBL2H3 cells increased the expression of MCP1 in B16F1 melanoma cells (Figure 7C) and lung macrophages (Figure 7E).…”

EVs from BALF—Mediators of Inflammation and Potential Biomarkers in Lung Diseases

“…For some patients, the potent chemotactic agent, C–C motif chemokine ligand 2 (CCL2) was also increased in PBMCs by exosomes. Interestingly, the exosome-driven increase of CCL2 was subsequently reduced by addition of a cysteinyl leukotriene receptor antagonist—montelukast [ 33 ], used as an asthma drug [ 34 ]. The abovementioned research showed possible roles of exosomes as mediators in inflammation progression and a potential target in sarcoidosis treatment.…”

Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses

“…In the same manner, focus could be placed on EXOSC2 (Exosome Component 2) targeted by the SARS-CoV2 protein NSP8, also known as ribosomal RNA-processing protein-4 (RRP4), an essential component of exosomes or extracellular vesicles acting as intercellular transmitters, and a scavenger of microbial RNA and infectious agents [95]. Broncho-alveolar lavage fluid of sarcoidosis patients showed increased levels of exosomes inducing various pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF (Tumor Necrosis Factor) alpha [96]. One may expect that any deficiency in autophagy-either autophagosome maturation or autolysosome formation-may induce a shift towards the endosomal-exosome pathway through the fusion of autophagosomes to multivesicular bodies (MVB) and the release in exosomes [97,98].…”