- Insights Figure for Anti-thymic stromal lymphopoietin antibody suppresses airway remodeling in asthma through reduction of MMP and CTGF. [Journal Article]
- PRPediatr Res 2019 Jun 13
- Digital Quantification of Epidermal Protein Expression in Paraffin-Embedded Tissue Using Immunohistochemistry. [Journal Article]
- MMMethods Mol Biol 2019 Jun 14
- Current methods of assessing immunohistochemistry center on semiquantitative visual grading scales. More objective methods utilizing digital quantification offer superior precision and, presumably, h…
Current methods of assessing immunohistochemistry center on semiquantitative visual grading scales. More objective methods utilizing digital quantification offer superior precision and, presumably, higher confidence with image comparison. However, their cost often remains prohibitive, and there is little customizability to separate subsections of interest in the tissue. Here we describe a method using two open-source software programs to analyze the intensity and density of signals in immunohistochemistry-stained tissue sections that account for tissue heterogeneity and allow for direct comparison between two samples. This method allows for quantitative assessment of epidermal protein expression. We herein demonstrate this workflow using an epidermal stain tothymic stromal lymphopoietin.
- Transcriptome profiling reveals Th2 bias and identifies endogenous itch mediators in poison ivy contact dermatitis. [Journal Article]
- JIJCI Insight 2019 Jun 11; 5
- In the United States, poison ivy exposure is the most common naturally occurring allergen to cause allergic contact dermatitis (ACD). The immune and pruritic mechanisms associated with poison ivy ACD…
In the United States, poison ivy exposure is the most common naturally occurring allergen to cause allergic contact dermatitis (ACD). The immune and pruritic mechanisms associated with poison ivy ACD remain largely unexplored. Here, we compared skin whole transcriptomes and itch mediator levels in mouse ACD models induced by the poison ivy allergen, urushiol, and the synthetic allergen, oxazolone. The urushiol model produced a Th2-biased immune response and scratching behavior, resembling findings in poison ivy patients. Urushiol-challenged skin contained elevated levels of the cytokine thymic stromal lymphopoietin (TSLP), a T-cell regulator and itch mediator, and pruritogenic serotonin (5-HT) and endothelin (ET-1), but not substance P (SP) or histamine. The oxazolone model generated a mixed Th1/Th2 response associated with increased levels of substance P, 5-HT, ET-1, but not TSLP or histamine. Injections of a TSLP monoclonal neutralizing antibody, serotonergic or endothelin inhibitors, but not SP inhibitors or antihistamines, reduced scratching behaviors in urushiol-challenged mice. Our findings suggest that the mouse urushiol model may serve as a translational model of human poison ivy ACD study. Inhibiting signaling by TSLP and other cytokines may represent alternatives to the standard steroid/antihistamine regimen for steroid-resistant or -intolerant patients and in exaggerated systemic responses to poison ivy.
- Pathogenesis of Atopic Dermatitis: Current Paradigm. [Journal Article]
- IJIran J Immunol 2019; 16(2):97-107
- Atopic dermatitis (AD) is characterized by skin inflammation, barrier dysfunction and chronic pruritus. In this review, recent advances in the pathogenesis of AD are summarized. Clinical efficacy of …
Atopic dermatitis (AD) is characterized by skin inflammation, barrier dysfunction and chronic pruritus. In this review, recent advances in the pathogenesis of AD are summarized. Clinical efficacy of the anti-IL-4 receptor antibody dupilumab implies that type 2 cytokines IL-4 and IL-13 have pivotal roles in atopic inflammation. The expression of IL-4 and IL-13 as well as type 2 chemokines such as CCL17, CCL22 and CCL26 is increased in the lesional skin of AD. In addition, IL-4 and IL-13 down-regulate the expression of filaggrin in keratinocytes and exacerbate epidermal barrier dysfunction. Keratinocytes in barrier-disrupted epidermis produce large amounts of thymic stromal lymphopoietin, IL-25 and IL-33, conducing to type 2 immune deviation via OX40L/OX40 signaling. IL-31, produced by type 2 T cells, is a cardinal pruritogenic cytokine. IL-4 and IL-13 also amplify the IL-31-mediated sensory nerve signal. These molecules are particularly important targets for future drug development for AD.
- Blockade of the CX3CL1-CX3CR1 Pathway Inhibits the Progress of Skin Inflammation, Fibrosis, and Vascular Injury in an Experimental Mouse Model of Systemic Sclerosis. [Journal Article]
- ARArthritis Rheumatol 2019 Jun 07
- CONCLUSIONS: Anti-CX3CL1mAb therapy may be a novel approach for early skin fibrosis in inflammation-driven fibrotic skin disorders such as SSc. This article is protected by copyright. All rights reserved.
- Protease-Activated Receptors 2-Antagonist Suppresses Asthma by Inhibiting Reactive Oxygen Species-Thymic Stromal Lymphopoietin Inflammation and Epithelial Tight Junction Degradation. [Journal Article]
- AAAllergy Asthma Immunol Res 2019; 11(4):560-571
- CONCLUSIONS: ROS generation and epidermal tight junction degradation are triggered by protease, followed by the induction of TSLP in allergic asthma. Our findings could suggest that PAR2-ant or anti-oxidants could be considered for allergic diseases as preventive alternatives.
- Similar immune mechanisms control experimental airway eosinophilia elicited by different allergens and treatment protocols. [Journal Article]
- BIBMC Immunol 2019 Jun 04; 20(1):18
- CONCLUSIONS: All the models studied were comparably dependent on adaptive CD4+ T cell responses and TSLP. In contrast, sex, NKT cells and TLR4 appeared to play subtler and more variable roles that were dependent on the type of allergen and mode of immunization and challenge. These results are consistent with clinical data suggesting a key role of CD4+ T cells and TSLP in patients with allergic asthma.
- Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling. [Journal Article]
- FIFront Immunol 2019; 10:921
- Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell ty…
Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (TH) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1β production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1β expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP.
- Impaired skin barrier function caused by reactive oxygen species in mice with colonic tumours. [Journal Article]
- COCutan Ocul Toxicol 2019 Jun 12; :1-7
- CONCLUSIONS: Superoxide anions may play an important role in the onset of the impaired skin barrier function in mice with colonic tumours.
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- Role of SNAREs in the Atopic Dermatitis-related Cytokine Secretion and Skin-Nerve Communication. [Journal Article]
- JIJ Invest Dermatol 2019 May 22
- The role of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) in atopic dermatitis (AD) is unknown. This study is envisioned to lead to the previously unreported SNARE f…
The role of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) in atopic dermatitis (AD) is unknown. This study is envisioned to lead to the previously unreported SNARE function in AD-related cytokine secretion and epidermis-nerve communication. Herein, we report that various cytokines were simultaneously upregulated and co-released in the innate immunity-activated primary human keratinocytes (phKCs). AD-related cytokines thymic stromal lymphopoietin (TSLP), endothelin-1 (ET-1) or inflammatory TNF-α activated distinct but overlapping sensory neurons. Interestingly, TNF-α potentiated TSLP-induced Ca2+-influx, whereas ET-1 caused itch-selective B-type natriuretic peptide (BNP) release. In phKCs, BNP upregulated genes promoting dermatological and neuroinflammatory diseases and conditions. VAMP3, SNAP-29 and syntaxin4 proved important in driving cytokine release from phKCs. Depletion of VAMP3 inhibited nearly all the cytokine release including TSLP and ET-1. Accordingly, VAMP3 co-occurred with ET-1 in AD patient skin. Our study pinpoints the pivotal role of SNAREs in mediating cytokine secretion related to AD. VAMP3 is identified as a suitable target for developing broad-spectrum anti-cytokine therapeutics for controlling itch and atopic skin inflammation.