Journal Of Investigative Dermatology

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The regulation of skin fibrosis in systemic sclerosis by extracellular ATP via P2Y2 purinergic receptor

Sun, 2018-11-04 00:00
Tissue injury/hypoxia and oxidative stress induced-extracellular ATP can act as a damage-associated molecular pattern molecules (DAMPs), which initiates inflammatory response. Objective was to elucidate the role of extracellular ATP in skin fibrosis in systemic sclerosis (SSc). We identified that hypoxia enhanced ATP release, and extracellular ATP enhanced IL-6 production more significantly in SSc fibroblasts than in normal fibroblasts. There were no significant differences of P2X and P2Y receptors expressions between normal and SSc fibroblasts.

Aging in skin of color: Disruption to elastic fiber organization is detrimental to skin’s biomechanical function

Sun, 2018-11-04 00:00
Skin aging is a complex process involving the additive effects of time-dependent intrinsic aging and changes elicited via skin’s interaction with the environment. Maintaining optimal skin function is essential for healthy aging across global populations; yet most research focuses on lightly-pigmented skin (Fitzpatrick phototypes I-III), with little emphasis on skin of color (Fitzpatrick phototypes V–VI). Here, we explore the biomechanical and histologic consequences of aging in black African-American volunteers.

The calcium-sensing receptor regulates epidermal intracellular Ca2+ signaling and re-epithelialization after wounding

Sun, 2018-11-04 00:00
Extracellular Ca2+ (Ca2+o) is a crucial regulator of epidermal homeostasis and its receptor, the Ca2+-sensing receptor (CaSR), conveys the Ca2+o signals to promote keratinocyte adhesion, differentiation, and survival via activation of intracellular Ca2+ (Ca2+i) and E-cadherin-mediated signaling. Here, we took genetic loss-of-function approaches to delineate the functions of CaSR in wound re-epithelialization. Cutaneous injury triggered a robust CaSR expression and a surge of Ca2+i in epidermis. CaSR and E-cadherin were co-expressed at the cell-cell membrane between migratory keratinocytes in the nascent epithelial tongues.

Pharmacological inhibition of serine palmitoyl transferase and sphingosine kinase-1/-2 inhibits Merkel Cell Carcinoma cell proliferation

Sat, 2018-11-03 00:00
The majority of Merkel cell carcinoma (MCC), a highly aggressive neuroendocrine cancer of the skin, is associated with Merkel cell polyomavirus (MCPyV) infection. Polyomavirus binding, internalization and infection is mediated by glycosphingolipids (GSL). Besides receptor function, bioactive sphingolipids (SL) are increasingly recognized as potent regulators of several hallmarks of cancer. MCPyV+ and MCPyV- cells express serine palmitoyltransferase (SPT) subunits and sphingosine kinase (SK)1/2 mRNA.

Potentiation of psoriasis-like inflammation by PCSK9

Fri, 2018-11-02 00:00
Psoriasis is a systemic inflammatory disease, associated with metabolic disorders, including high level of low-density lipoprotein(LDL). Proprotein convertase subtilisin/kexin 9 (PCSK9), promoting the degradation of LDL receptors, and therefore the increased concentration of circulating LDL, is also involved in inflammation. This study aims to examine the role of PCSK9 in psoriasis and to investigate the potential of topically applying siRNA targeting Pcsk9 as a psoriasis treatment. We investigated the expression of PCSK9 in lesions of psoriasis patients, the imiquimod (IMQ) induced psoriatic reactions in Pcsk9 knockout and Pcsk9 siRNA treated mice, and also used cultured human keratinocytes to investigate the role of PCSK9 on regulating cell proliferation and apoptosis.

Culprit drugs induce specific IL-36 overexpression in Acute Generalized Exanthematous Pustulosis

Fri, 2018-11-02 00:00
Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remains incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis. Here, we show that IL-36 cytokines, in particular IL-36γ, is highly expressed in lesional skin of AGEP patients, keratinocytes and macrophages being a major source of IL-36γ.

Granzyme K Expressed by Classically Activated Macrophages Contributes to Inflammation and Impaired Remodeling

Fri, 2018-11-02 00:00
Granzyme K (GzmK), traditionally described as a pro-apoptotic, granule-secreted serine protease, has been proposed to promote inflammation. Found at low levels in the plasma of healthy individuals, GzmK is markedly elevated in response to sepsis and infection. In the present study we investigated the role of GzmK in inflammation and remodeling in response to thermal injury. In human burn tissue, GzmK was elevated compared to normal skin, with expression predominantly found in macrophages. GzmK was expressed and secreted by cultured human classically-activated macrophages.

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