Keratinocyte-derived microvesicle particles mediate ultraviolet B radiation–induced systemic immunosuppression

Abstract

A complete carcinogen, Ultraviolet B radiation (290-320 nm; UVB), is the major cause of skin cancer. UVB-induced systemic immunosuppression that contributes to photocarcinogenesis is due to the glycerophosphocholine-derived lipid mediator Platelet-activating factor. A major question in photobiology is how UVB radiation, which only absorbs appreciably in the epidermal layers of skin, can generate systemic effects. UVB exposure and PAF Receptor (PAFR) activation in keratinocytes induce large amounts of microvesicle particle (extracellular vesicles 100-1000nm; MVP) release. MVPs released from skin keratinocytes in vitro in response to UVB (UVB-MVP) are dependent upon the keratinocyte PAFR. The present studies used both pharmacologic and genetic approaches in cells and mice to determine that both the PAFR and enzyme acid sphingomyelinase (aSMase) were necessary for UVB-MVP generation. Discovery that the calcium-sensing receptor is a keratinocyte-selective MVP marker allowed us to determine that UVB-MVP leaving the keratinocyte can be found systemically in mice and in human subjects following UVB. Moreover, UVB-MVP contain bioactive contents including PAFR agonists which allow them to serve as effectors for UVB downstream effects, in particular UVB-mediated systemic immunosuppression.

Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure

“…It is also consistent with narrow band UVB dosages utilized in the clinical setting (500–1000 mJ/cm 2 ) [ 56 ]. Other studies examining the effects of UVB on different types of cells, including the keratinocytes, have utilized similar fluences [ [57] , [58] , [59] , [60] ].…”

The promise of exosome applications in treating central nervous system diseases

“…26 We isolated endothelial cell-derived EXs from plasma by using endothelial cell-specific markers (CD144/CD105) and EPC-EXs with EPC-specific markers (CD34/KDR). Recently, Liu et al 27 identified keratinocyte extracellular vesicles with keratinocyte marker calcium-sensing receptor from human skin biopsy tissue and plasma. EX-mediated communication process mainly includes release, transport, capture, internalization, and regulation.…”

Evidence for Systemic Reactive Oxygen Species in UVB‐mediated Microvesicle Formation

“…Recent studies have implicated subcellular microvesicle particles (100-1000 nm; MVP) in how the skin responds to ultraviolet B (UVB) radiation (reviewed in (3,4)). Keratinocytes generate MVP in response to multiple stressors such as UVB and thermal burn injury (4)(5)(6)(7). Once dismissed as unimportant cellular debris, microvesicle particles have been suggested to serve a signaling function through their abilities to carry bioactive agents including proteins, lipids and nucleic acids.…”

“…Moreover, if MVP underlie some of UVB effects, this could provide potential therapeutic targets. In particular, the mechanisms by which UVB generates MVP involve the generation of the lipid mediator platelet-activating factor (1-alkyl-2-acetyl glycerophosphocholine; PAF) acting through its G-protein-coupled receptor (PAFR) as well as the ceramide-generating enzyme acid sphingomyelinase (7). As UVB generates both PAF and non-enzymatic PAF-like lipids via reactive oxygen species (ROS) (9), the present study was designed to test the hypothesis that UVB generates MVP in human skin through its ability to function as a pro-oxidative stressor.…”

“…First, we tested if whole-body narrow-band UVB (NB-UVB; 311 nm) irradiation from patients undergoing medical phototherapy, which we have previously reported generates elevated levels of MVP expressing a keratinocyte-selective marker in the serum (7), results in a systemic pro-oxidative stress by measuring the formation of isoprostanes and 8-hydroxydeoxyguanosine in the urine of treated subjects. Second, we conducted an interventional clinical study testing if a seven-day course of oral antioxidant vitamins C and E would diminish MVP generated in the skin following local UVB exposure.…”