Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

Abstract

ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasmaderived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.

Plasma exosomal miRNAs involved in endothelial injury in microscopic polyangiitis patients

“…A few studies indicate that miRNAs are involved in the inflammatory response of AAV, which may facilitate the endothelial injury. It was 14 demonstrated that miRNA‐634 was significantly upregulated in the peripheral blood of active AAV patients and induced a pro‐inflammatory phenotype of macrophages. miRNA‐155 was upregulated in the kidney of patients with ANCA‐associated crescentic glomerulonephritis 15 .…”

Plasma Ang2 and ADAM17 levels are elevated during clinical malaria; Ang2 level correlates with severity and expression of EPCR-binding PfEMP1

“…We also observed a weak correlation between Ang2 and ADAM17. Ang2 is released to the plasma from WPBs of activated endothelial cells21, and ADAM17 is co-localized with Ang2 in the WBPs26, which could explain this correlation. However, as ADAM17 plasma levels seem to be elevated as a response to disease in general, whereas Ang2 plasma levels are particularly increased in SM, it seems unlikely that the increase of ADAM17 plasma levels was primarily due to activation of endothelial cells and subsequent release of WPB.…”

“…However, the origin of ADAM17 in plasma is unknown. Secretion of enzymatically active ADAM17 on extracellular microparticles has been found in the plasma and associated with disease activity of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis26. ANCA-associated vasculitis, as malaria, features an excessive inflammatory response, which leads to the shedding of adhesion molecules and cytokines, such as TNFα3132.…”

“…In addition to the presence on leukocytes, ADAM17 is also found along with Ang2 in the WPBs of endothelial cells26. Little is known about ADAM17 in malaria, but the cleavage of host receptors specifically utilized by IEs in severe malaria patients and cytokines, such as TNFα, which are increased in SM, suggests ADAM17 plays a role in malaria pathogenesis.…”

Decoding the enigma of antiviral crisis: Does one target molecule regulate all?

“…The ability of ADAM-17 to control and influence other molecules of the immune system is now the subject of extensive investigation. It is now well established that ADAM-17 mediated shedding of cell surface molecules are involved in progression of multiple pathological condition [82,[93][94][95][96]. ADAM-17-induced IL-6 trans-signaling-mediated pathogenesis is now known to be a common feature of inflammatory bowel disease as well as of many respiratory diseases [97][98][99][100][101].…”