Endothelial microparticles carrying hedgehog-interacting protein induce continuous endothelial damage in the pathogenesis of acute graft-versus-host disease

Abstract

Accumulating evidence suggests that endothelial microparticles (EMPs), a marker of endothelial damage, are elevated in acute graft-versus-host disease (aGVHD), and that endothelial damage is implicated in the pathogenesis of aGVHD, but the mechanisms remain elusive. In this study, we detected the plasma EMP levels and endothelial damage in patients and mice with aGVHD in vivo and then examined the effects of EMPs derived from injured endothelial cells (ECs) on endothelial damage and the role of hedgehog-interacting protein (HHIP) carried by EMPs in these effects in vitro. Our results showed that EMPs were persistently increased in the early posttransplantation phase in patients and mice with aGVHD. Meanwhile, endothelial damage was continuous in aGVHD mice, but was temporary in non-aGVHD mice after transplantation. In vitro, EMPs induced endothelial damage, including increased EC apoptosis, enhanced reactive oxygen species, decreased nitric oxide production and impaired angiogenic activity. Enhanced expression of HHIP, an antagonist for the Sonic hedgehog (SHH) signaling pathway, was observed in patients and mice with aGVHD and EMPs from injured ECs. The endothelial damage induced by EMPs was reversed when the HHIP incorporated into EMPs was silenced with an HHIP small interfering RNA or inhibited with the SHH pathway agonist, Smoothened agonist. This work supports a feasible vicious cycle in which EMPs generated during endothelial injury, in turn, aggravate endothelial damage by carrying HHIP into target ECs, contributing to the continuously deteriorating endothelial damage in the development of aGVHD. EMPs harboring HHIP would represent a potential therapeutic target for aGVHD.

Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury

“…Clinical studies indicate that MP in the blood are primarily derived from platelets, with much smaller fractions released from erythrocytes, granulocytes, monocytes, lymphocytes, and endothelial cells [18, 19, 21, 38, 39]. Recent studies have highlighted the potential systemic pathological effects of MP following brain injury, including brain-trauma-associated coagulopathy [21].…”

AT2R deficiency mediated podocyte loss via activation of ectopic hedgehog interacting protein (Hhip) gene expression

“…Hh pathways [6,[12][13][14][15][16][17][18]. The importance of Hhip is highlighted by the findings that (i) Hhip overexpression in chondrocytes leads to severe skeletal defects [6,14]; (ii) deficient Hhip expression results in lung and pancreas malformations [6,14]; and (iii) altered Hhip gene expression is linked to several human diseases, such as pancreatitis [19], chronic obstructive pulmonary disease [18,20], and various tumors [21,22].…”

Desert Hedgehog-driven endothelium integrity is enhanced by Gas1 but negatively regulated by Cdon

“…Notably, Gas1 is not detected in HBMECs. Since the role of endothelial Hhip has already been reported in several papers (Agrawal, Kim, et Kwon 2017;Sekiguchi et al 2012;Nie et al 2016), we focused our investigations on Gas1 and Cdon and confirmed their endothelial expression via immunostaining ( Figure 1B). Interestingly, while TNFα inhibits Gas1 mRNA expression in HUVECs (Supplemental Figure 2A), it increases Cdon mRNA expression (Supplemental Figure 2B).…”