Plasma Corticotropin-Releasing Factor Receptors and B7-2+ Extracellular Vesicles in Blood Correlate with Irritable Bowel Syndrome Disease Severity

Abstract

Extracellular vesicles (EVs) are composed of bilayer membranes that are released by different cell types and are present in bodily fluids, such as blood, urine, and bile. EVs are thought to play a key role in intracellular communication. Based on their size and density, EVs are classified into small, medium, or large EVs. Cargo composition in EVs reflects physiological changes in health and disease. Patients with irritable bowel syndrome (IBS) exhibit visceral hypersensitivity and mood disorders. Stressful episodes often precede disease symptoms in IBS patients. Stress-induced symptoms include, but are not limited to, abdominal pain and mood swings. Perceived stress responses are mediated by two known G protein-coupled receptors (GPCRs), corticotropin-releasing factor receptor 1 and 2 (CRFRs). CRFRs belong to the Class B secretin receptor family of GPCRs. Here, we show that CRFRs were present in human and murine plasma, and in EVs purified from mouse serum. CRFRs were present in plasma from IBS patients and healthy controls. EVs secreted from immune cells influence both adaptive and innate immune responses via exchange of EVs between different immune cell types. B7-2 (CD86), a plasma membrane antigen-presenting protein, is present on EVs secreted from dendritic, B-, and mast cells, whereas CD9 is present on EVs secreted from dendritic and intestinal epithelial cells. We found that plasma CRFR levels positively correlated with B7-2+ EVs (R = 0.8597, p < 0.0001), but no association was seen with CD9+ EVs. Plasma CRFRs expression negatively correlated with IBS severity scores. Our data suggests that plasma EVs from immune cells carry CRFRs as cargos and influence cell-cell communication in health and disease.

Adenosine and Metabotropic Glutamate Receptors Are Present in Blood Serum and Exosomes from SAMP8 Mice: Modulation by Aging and Resveratrol

“…The higher molecular weight observed in this receptor could be due to glycosylation or related-mechanism likely to facilitate their transport in blood serum. In accordance, circulating CRF receptor I/II were also detected at a discrete but higher molecular weight in human blood serum [32]. Regarding mGluR 5 , it was found a band at 125-130 kDa, which is in line with the predicted weight estimated by the manufacturer's indications, suggesting that this receptor might be released as a full-length molecule.…”

“…The presence of different GPCRs in blood serum has been evidenced before. Corticotropin releasing-factor receptors I/II (CRF receptor I/II) were reported as circulating receptors in extracellular vesicles (EVs) from blood serum [32]. Additionally, the purinergic receptor P2 × 7 was found as EVs cargo in human blood serum.…”

“…However, it has been recently reported the presence of receptors in circulation. The biological significance of those results remains to be clarified but the authors reported a potential correlation with some particular diseases [31,32], suggesting a predictive value in diagnosis. Now, we show for the first time the presence of ARs and mGluRs, as well as their corresponding endogenous ligands, in blood serum and derived exosomes in SAMP8 mice.…”

“…However, it has been recently reported the presence of receptors in circulation. The biological significance of those results remains to be clarified but the authors reported a potential correlation with some particular diseases [ 31 , 32 ], suggesting a predictive value in diagnosis.…”

Cell–cell communication: old mystery and new opportunity

“…Extracellular vesicles-mediated cell-cell communication impacts physiological changes in health and disease. For example, vesicles secreted from immune cells change adaptive and innate immune responses via exchange of vesicles between different immune cell types in patients with irritable bowel syndrome (Hagiwara et al 2019). This study indicated that the vesicle contents are relatively specific on basis of cell phenotype and function.…”