Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis

Guttman‐Yassky, Emma; Suárez‐Fariñas, Mayte; Chiricozzi, Andrea; Nograles, Kristine; Shemer, Avner; Fuentes‐Duculan, Judilyn; Cardinale, Irma; Lin, Peng; Bergman, Reuven; Bowcock, Anne M.; Krueger, James G.

doi:10.1016/j.jaci.2009.09.031

Cited by 231 publications

(238 citation statements)

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“…These diseases are prevalent, affecting ∼7-10% of the total population, but their etiology remains incompletely understood. Characterization of altered gene expression patterns has provided insights into the pathophysiology of each disorder (9). In this study, we demonstrated up-regulation of Sprr2d, Defb3, Cdsn, and S100a9 expression in K14cre;Dlx3 Kin/f skin, indicating overlap in gene expression between this mouse model and the PS gene expression signature (9,22).…”

Section: Discussionmentioning

confidence: 53%

“…Characterization of altered gene expression patterns has provided insights into the pathophysiology of each disorder (9). In this study, we demonstrated up-regulation of Sprr2d, Defb3, Cdsn, and S100a9 expression in K14cre;Dlx3 Kin/f skin, indicating overlap in gene expression between this mouse model and the PS gene expression signature (9,22). Moreover, marked down-regulation of Dlx3 expression was detected in human psoriatic lesions, suggesting that the lack of Dlx3 transcriptional function is potentially involved in the pathophysiology of human inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Up-regulation of Klk family members in K14cre;Dlx3 Kin/f skin may indicate activation of pathways involved in barrier function and innate immunity. Interestingly, Klk5 and Klk6 expression was up-regulated in PS skin compared with normal and AD skin (9).…”

Section: Mice Lacking Dlx3 In Epidermis Exhibit Abnormalities In Epidmentioning

confidence: 93%

“…To identify possible similarities between human inflammatory skin diseases and the skin inflammation in K14cre;Dlx3 Kin/f mice, qPCR analysis was performed for genes composing signatures for PS and AD (9,10). These results showed sustained up-regulation of Sprr2d, Defb3, and S100a9 expression in the K14cre;Dlx3 Kin/f mice (Fig.…”

Section: Il-17-expressing T Cells and Leukocytes Are Increased In Thementioning

confidence: 99%

“…Most notably, inflamed skin generally exhibits abnormal keratinocyte differentiation, disrupted barrier function, and/or immunocyte abnormalities (9)(10)(11). Studying key genes that are active in immunologic functions as well as epidermal homeostasis will provide insight into the intricate regulatory networks involved in complex inflammatory skin diseases.…”

mentioning

confidence: 99%

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Epidermal ablation of Dlx3 is linked to IL-17–associated skin inflammation

Hwang

Kita

Kwon

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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In an effort to understand the role of Distal-less 3 (Dlx3) in cutaneous biology and pathophysiology, we generated and characterized a mouse model with epidermal ablation of Dlx3. K14cre;Dlx3 Kin/f mice exhibited epidermal hyperproliferation and abnormal differentiation of keratinocytes. Results from subsequent analyses revealed cutaneous inflammation that featured accumulation of IL-17-producing CD4 + T, CD8 + T, and γδ T cells in the skin and lymph nodes of K14cre;Dlx3 Kin/f mice. The gene expression signature of K14cre;Dlx3 Kin/f skin shared features with lesional psoriatic skin, and Dlx3 expression was markedly and selectively decreased in psoriatic skin. Interestingly, cultured Dlx3 null keratinocytes triggered cytokine production that is potentially linked to inflammatory responses in K14cre;Dlx3 Kin/f mice. Thus, Dlx3 ablation in epidermis is linked to altered epidermal differentiation, barrier development, and IL-17-associated skin inflammation. This model provides a platform that will allow the systematic exploration of the contributions of keratinocytes to cutaneous inflammation.barrier function | psoriasis | inflammatory diseases | homeobox transcription factor | mouse model

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Mice Lacking Dlx3 In Epidermis Exhibit Abnormalities In Epidmentioning

confidence: 93%

Section: Il-17-expressing T Cells and Leukocytes Are Increased In Thementioning

confidence: 99%

mentioning

confidence: 99%

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Epidermal ablation of Dlx3 is linked to IL-17–associated skin inflammation

Hwang

Kita

Kwon

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Use of Tape Strips to Detect Immune and Barrier Abnormalities in the Skin of Children With Early-Onset Atopic Dermatitis

et al. 2019

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IMPORTANCE Molecular profiling of skin biopsies is the criterion standard for evaluating the cutaneous atopic dermatitis (AD) phenotype. However, skin biopsies are not always feasible in children. A reproducible minimally invasive approach that can track cutaneous disease in pediatric longitudinal studies or clinical trials is lacking. OBJECTIVE To assess a minimally invasive approach using tape strips to identify skin biomarkers that may serve as a surrogate to biomarkers identified using whole-tissue biopsies. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study of 51 children younger than 5 years recruited children with moderate to severe AD and children without AD from the dermatology outpatient clinics at a children's hospital. Sixteen tape strips were serially collected from the nonlesional and lesional skin of 21 children who had AD and were less than 6 months from disease initiation and from the normal skin of 30 children who did not have AD between January 22, 2016, and April 20, 2018. MAIN OUTCOMES AND MEASURES Gene and protein expression were evaluated using quantitative real-time polymerase chain reaction and immunohistochemistry. RESULTS A total of 51 children younger than 5 years were included in the study; 21 children had moderate to severe AD with less than 6 months of disease duration, and 30 children did not have AD. Of the 21 children with AD, the mean (SD) age was 1.7 (1.7) years, and most were male (15 [71.4%] and white (15 [71.4%]). Of the 30 children without AD, the mean (SD) age was 1.8 (2.0) years, and most were female (20 [66.7%]) and white (22 [73.3%]). Seventy-seven of 79 evaluated immune and barrier gene products were detected (gene detection rate, 97%) in 70 of 71 tape strips (sample detection rate, 99%), with 53 of 79 markers differentiating between children with lesional and/or nonlesional AD from children without AD. Many cellular markers of T cells (CD3), AD-related dendritic cells (Fc ε RI and OX40 ligand receptors), and key inflammatory (matrix metallopeptidase 12), innate (interleukin 8 [IL-8] and IL-6), helper T cell 2 (T H 2; IL-4, IL-13, and chemokines CCL17 and CCL26), and T H 17/T H 22 (IL-19, IL-36G, and S100A proteins) genes were significantly increased in lesional and nonlesional AD compared with tape strips from normal skin. For example, IL-4 mean (SE) for lesional was −15.2 (0.91) and normal was −19.5 (0.48); P < .001. Parallel decreases occurred in epidermal barrier gene products (FLG, CLDN23, and FA2H) and negative immune regulators (IL-34 and IL-37). For example, the decrease for FLG lesional was mean (SE) −2.9 (0.42) and for normal was 2.2 (0.45); P < .001. Associations were found between disease severity or transepidermal water loss and T H 2 (IL-33 and IL-4R) and T H 17/T H 22 (IL-36G and S100As) products in lesional and nonlesional AD skin (evaluated using the SCORing Atopic Dermatitis, Eczema Area and Severity Index, and Pruritus Atopic Dermatitis Quickscore tools). CONCLUSIONS AND RELEVANCE In this study, tape strips provide a minimally invasive alte...

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