The contribution of epithelial-to-mesenchymal transitions (EMT) in both developmental and pathological conditions has been widely recognized and studied. In a parallel process, governed by a similar set of signaling and transcription factors, endothelial-to-mesenchymal transitions (EndoMT) contribute to heart valve formation and the generation of cancer-associated-fibroblasts. During angiogenic sprouting endothelial cells express many of the same genes and break down basement membrane, however they retain intercellular junctions and migrate as a connected “train” of cells rather than as individual cells. This has been termed a partial EndoMT. A key regulatory check-point determines whether cells undergo a full or a partial EMT/EndoMT, however, very little is known about how this switch is controlled. Here we discuss these developmental/pathologic pathways, with a particular focus on their role in vascular biology.

Cystathionine-β-synthase (CBS) catalyzes the rate-limiting step in the transsulfuration pathway for the metabolism of homocysteine (Hcy) in the kidney. Our recent study demonstrates that ischemia-reperfusion reduces the activity of CBS leading to Hcy accumulation in the kidney, which in turn contributes to renal injury. CBS is also capable of catalyzing the reaction of cysteine with Hcy to produce hydrogen sulfide (H2S), a gaseous molecule that plays an important role in many physiological and pathological processes. The aim of the present study was to examine the effect of ischemia-reperfusion on CBS-mediated H2S production in the kidney and to determine whether changes in the endogenous H2S generation had any impact on renal ischemia-reperfusion injury. The left kidney of Sprague-Dawley rat was subjected to 45-min ischemia followed by 6-h reperfusion. The ischemia-reperfusion caused lipid peroxidation and cell death in the kidney. The CBS-mediated H2S production was decreased, leading to a significant reduction in the renal H2S level. The activity of cystathionine-γ-lyase, another enzyme responsible for endogenous H2S generation, was not significantly altered in the kidney upon ischemia-reperfusion. Partial restoration of CBS activity by intraperitoneal injection of the nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide not only increased renal H2S levels but also alleviated ischemia-reperfusion-induced lipid peroxidation and reduced cell damage in the kidney tissue. Furthermore, administration of an exogenous H2S donor, NaHS (100 μg/kg), improved renal function. Taken together, these results suggest that maintenance of tissue H2S level may offer a renal protective effect against ischemia-reperfusion injury.

Ubiquitination of MHCII molecules on dendritic cells is essential for the development of natural regulatory T cells

The high-affinity IgE receptor FcεRI is constitutively expressed in mast cells and basophils and is required for transmitting stimulatory signals upon engagement of IgE-bound allergens. FcεRI is also constitutively expressed in dendritic cells (DCs) and monocytes in humans; however, the specific functions of the FcεRI expressed by these cells are not completely understood. Here, we found that FcεRI expressed by human blood DC antigen 1-positive (BDCA1 + ) DCs and monocytes, but not basophils, traffics to endolysosomal compartments under steady-state conditions. Furthermore, IgE bound to FcεRI on BDCA1 + DCs was rapidly endocytosed, transported to the lysosomes, and degraded in vitro. IgE injected into mice expressing human FcεRIα (FCER1A-Tg mice) was endocytosed by conventional DCs and monocytes, and endocytosis was associated with rapid clearance of circulating IgE from these mice. Importantly, this rapid IgE clearance was dependent on monocytes or DCs but not basophils. These findings strongly suggest that constitutive internalization of human FcεRI by DCs and monocytes distinctively contributes to serum IgE clearance.