Journal Of Investigative Dermatology

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The phosphatase regulator NIPP1 restrains chemokine-driven skin inflammation

Mon, 2020-01-20 00:00
NIPP1 is a ubiquitously expressed nuclear protein that regulates functions of protein Ser/Thr phosphatase-1 in cell proliferation and lineage specification. The role of NIPP1 in tissue homeostasis is not fully understood. Here we show that the selective deletion of NIPP1 in mouse epidermis resulted in epidermal hyperproliferation, a reduced adherence of basal keratinocytes and a gradual decrease in the stemness of hair follicle stem cells, culminating in hair loss. This complex phenotype was associated with chronic sterile skin inflammation and could be partially rescued by dexamethasone treatment.

Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor, PF 06700841, Reveal Reduction of Skin Inflammation in Plaque Psoriasis

Mon, 2020-01-20 00:00
The interleukin (IL)-23/T-helper type 17 cell axis is a target for psoriasis. The tyrosine kinase 2 (TYK2)/Janus kinase 1 (JAK1) inhibitor, PF-06700841, will directly suppress TYK2-dependent IL-12 and IL-23 signaling and JAK1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n=30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n=14) or 100 mg (n=7) PF-06700841, or placebo (n=9) for 28 days.

Specific IgA and CLA+ T-cell IL-17 response to Streptococcus pyogenes in psoriasis

Mon, 2020-01-20 00:00
Streptococcus pyogenes tonsillar infection is well-known to trigger and exacerbate psoriasis lesions in both guttate and plaque forms of the disease. Although mucosal and cutaneous tissues are closely involved in psoriasis pathology, the interaction between their specific immune responses has not been deeply explored. This work aims to address and characterize the presence of humoral responses against Streptococcus pyogenes in psoriasis patients and its putative association with cytokine responses detected in vitro in our psoriasis ex vivo model, based on the coculture of CLA+/- T cells with autologous epidermal cells.

Uniting Discovery and Care: The Role of Pharmaceutical Companies in Research, Clinical Studies and Patient Care

Mon, 2020-01-20 00:00
In an era of increased complexity of clinical research, a demand for personalized medicine, an increasing value of diversity, a focus on digital health, and a call for patient-centricity, the discovery and development of new medicines, more than ever, is dependent on collaboration between multiple stakeholders (Figure 1).

Activated Hgf-Met signaling cooperates with oncogenic Braf to drive primary cutaneous melanomas and angiotropic lung metastases in mice

Mon, 2020-01-20 00:00
Oncogenic mutations in the Braf-kinase gene represent the most frequent genomic driver in acquired melanocytic nevi and in cutaneous melanomas. It is currently thought that oncogene-induced senescence and cell cycle arrest limit the ability of oncogenic Braf to promote melanocyte proliferation in benign nevi. The molecular and cellular mechanisms that allow an oncogenic Braf mutation to fully transform melanocytes into invasively growing melanoma cells that are able to metastasize systemically are only partially understood.

IL-17E (IL-25) and IL-17A differentially affect the functions of human keratinocytes

Sat, 2020-01-18 00:00
Our group has recently shown that keratinocyte-derived IL-17E (IL-25), one of six members of the IL-17 family, is overexpressed in lesional psoriatic skin and is involved in its pathophysiology. We show here that IL-22 enhances IL-17E production in human keratinocytes and that these cells display a complete IL-17E receptor at their surface, which expression is further induced by IL-17A, indicating a potential autocrine effect of IL-17E. Therefore, we addressed the impact of IL-17E on the function of human primary keratinocytes.

Activation of SIRT1 Enhances Epidermal Permeability Barrier Formation Through Ceramide Synthases 2 and 3-Dependent Mechanisms

Fri, 2020-01-17 00:00
We recently demonstrated that a synthetic silent information regulator T1 (SIRT1) activator, Hexacarboxymethyldipeptide-12 (HMD-12), protects the skin against damages caused by ultraviolet irradiation (Lim et al., 2017). In addition, in one study, SIRT1 activation has been shown to promote keratinocyte (KC) differentiation, which is a critical process for the formation of the epidermal barrier, but the cellular mechanism underlying the SIRT1-mediated KC differentiation has remained unknown (Blander et al., 2009).

JAK inhibition prevents bleomycin-induced fibrosis in mice and is effective in morphea patients

Thu, 2020-01-16 00:00
To the Editor, Morphea is an autoimmune disease that causes fibrosis of the skin that may result in significant morbidity. Eosinophilic fasciitis (EF) may be considered a deeper form of morphea, and features of both morphea and EF can be present in individual patients. Morphea and EF have been postulated to have pathogenic features that overlap with systemic sclerosis (Laxer and Zulian, 2006). In these diseases, dysregulated immune responses are thought to induce fibrosis (Torok et al., 2019). Treatment of these diseases with non-specific immunosuppressants such as corticosteroids is often ineffective and associated with toxicity.

Decreased CCN3 in Systemic Sclerosis endothelial cells contributes to impaired angiogenesis

Thu, 2020-01-16 00:00
Systemic sclerosis (SSc) is a rare and severe connective tissue disease combining auto-immune and vasculopathy features, ultimately leading to organ fibrosis. Impaired angiogenesis is an often silent and life-threatening complication of the disease. We hypothesize that CCN3 (NOV), a member of the CCN family of extra-cellular matrix proteins, which is an antagonist of the pro-fibrotic protein CCN2 (CTGF) as well as a pro-angiogenic factor, is implicated in SSc pathophysiology.We performed skin biopsies on 26 SSc patients, both in fibrotic and non-fibrotic areas for 17 patients, and collected 18 healthy control skin specimens, for immunohistochemistry and cell culture.

B cell-targeted immunotherapy limits tumor growth, enhances survival and prevents lymph node metastasis of UV-induced keratinocyte cancers in mice

Thu, 2020-01-16 00:00
Ultraviolet (UV)-induced DNA damage, suppression of anti-tumor immune responses and promotion of cutaneous inflammation underly the skin tumor promoting activities of sunlight. Targeting the immune regulatory pathways activated by UV is proving a highly effective therapeutic strategy to treat both melanoma (Hodi et al., 2010) and keratinocyte cancers (Day et al., 2017). However, many of these first generation check-point inhibitors come with significant side effects including increased risk of autoimmune toxicities (Phan et al., 2003) and rejection of allografts in some transplant recipients at high risk of metastatic skin cancer (Abdel-Wahab et al., 2019).

MDA5+ Dermatomyositis Is Associated with Stronger Skin Type I Interferon Transcriptomic Signature with Upregulation of IFN-κ Transcript

Thu, 2020-01-16 00:00
Dermatomyositis (DM) is a chronic inflammatory and autoimmune disorder belonging to the idiopathic inflammatory myopathies affecting primarily skin and muscle with variable extent. Disease mechanism comprehension is growing, with a pivotal role of both the innate and adaptive immune system and involvement of both cellular and humoral actors (Nagaraju and Lundberg, 2011). The immune transcriptomic signature of DM is characterized by a type I IFN signature in peripheral blood mononuclear cells, muscle, and skin, which has been shown to correlate with disease activity (Baechler et al., 2011; Walsh et al., 2007; Wong et al., 2012); consequently, targeting type I IFN seems to represent a novel therapeutic approach in DM (Higgs et al., 2014).

The value of item banks, CAT and PROMIS for dermatology

Mon, 2020-01-13 00:00
Patient-Reported Outcome Measures (PROMs) have been used in research for decades. Increasingly PROMs are being used in clinical practice to systematically address, and monitor over time, how patients feel and function in daily life. Using PROMs empowers patients to discuss health issues, which improves communication and contributes to informed decision making, in line with the principles of delivering value-based health care (Rotenstein et al., 2017).

Translational research and drug development in psoriasis by collaborative efforts of academia and industry

Mon, 2020-01-13 00:00
We are witnessing the broad implementation of new treatments for psoriasis, resulting from the research on genetics and pathogenesis and from the development of new targeted treatments.

Rare loss-of-function mutation in SERPINA3 in generalized pustular psoriasis

Mon, 2020-01-13 00:00
Generalized pustular psoriasis (GPP) represents a rare pustular disease manifesting as a multi-systemic inflammation in a chronic or episodic course, sometimes as life-threatening incidents. Bi-allelic IL36RN mutations are known to be disease-causing/ -contributing in 21-41% of GPP patients (Hussain et al., 2015, Marrakchi et al., 2011, Mossner et al., 2018, Onoufriadis et al., 2011, Sugiura et al., 2013). IL-36 binds to the IL-36-receptor(IL-36R)-complex, thereby triggering the activation of MAPK and NF-κB, resulting in production of pro-inflammatory cytokines.

Differences in staining for neutrophil elastase and its controlling inhibitor SLPI reveal heterogeneity among neutrophils in psoriasis.

Mon, 2020-01-13 00:00
Neutrophils are broadly classified into conventional neutrophils (PMNs) and low density granulocytes (LDGs). LDGs are better than PMNs in the generation of NETs, which may contribute to the pathology of autoimmune diseases. We hypothesized that LDGs and PMNs differ in levels of unrestrained neutrophil elastase (NE) that supports NET generation. Here, we show that individuals with psoriasis contain elevated levels of LDGs and that in contrast to PMNs, LDGs display higher staining for NE and lower staining for its inhibitor SLPI.

Calcium-inducible MAPK/AP-1 signaling drives semaphorin 3A expression in normal human epidermal keratinocytes

Mon, 2020-01-13 00:00
Epidermal keratinocytes express semaphorin (Sema) 3A, which is involved in the regulation of cutaneous innervation. However, the mechanisms underlying the intracellular signaling of Sema3A expression in keratinocytes remain unknown. We herein investigated signaling mechanisms for the induction of Sema3A expression in normal human epidermal keratinocytes (NHEKs). Sema3A expression transiently increased in calcium-stimulated NHEKs, but markedly decreased in terminally differentiated NHEKs. Sema3A mRNA mainly localized in the stratum basale and stratum suprabasale of the epidermis.

A small molecule CCR2 antagonist depletes tumor macrophages and synergizes with anti-PD1 in a murine model of cutaneous T cell lymphoma (CTCL)

Mon, 2020-01-13 00:00
Tumor-associated macrophages (TAMs) recruited from blood monocytes are key in establishing an immunosuppressive tumor microenvironment (TME) for supporting tumor growth. We hypothesize that blocking monocyte trafficking (through inhibition of specific chemokine receptors) into skin can influence tumor development. Herein, we examine the effects of oral administration of a small molecule inhibitor for CCR2, CCR2i, which blocks CCR2-mediated chemotaxis of monocytes in a syngeneic mouse T cell lymphoma in skin.

Steroid receptor RNA activator (SRA), a long noncoding RNA, activates p38, facilitates epithelial mesenchymal transformation, and experimental melanoma metastasis

Mon, 2020-01-13 00:00
Melanoma metastasis signals dismal prognosis even with current checkpoint inhibitors. Long noncoding RNAs (lncRNAs) regulate dynamic metastasis in several cancers, including melanoma. We become interested in a lncRNA, SRA (steroid receptor RNA activator), because it is the first lncRNA also encoding a conserved protein SRAP and regulates progression of prostate and breast cancers. We investigated how SRA mediates melanoma proliferation, migration, invasion, EMT, and metastasis by RNA interference.

MiR-101-3p down-regulates TLR2 expression, leading to reduction in cytokines production by T. pallidum-stimulated macrophages

Fri, 2020-01-10 00:00
Treponema pallidum (Tp) infection-induced immune responses can cause tissue damage. However, the underlying mechanism by which Tp infection induces immune response is unclear. Recent studies suggest a regulatory role of microRNAs (miRNAs) in host immunity. We assessed whether miRNAs also have a regulatory role in immune response to Tp infection in vitro. Our results showed that miR-101-3p levels were significantly higher in peripheral blood mononuclear cells of patients with primary syphilis and those in the serofast state, while TLR2 levels were higher in syphilitic patients than in healthy controls.