Distinct association of genetic variations of vascular endothelial growth factor, transforming growth factor‐β, and fibroblast growth factor receptors with atopy and airway hyperresponsiveness

Park, Han-Kyul; Park, H.W.; Jeon, Seong Gyu; Shin, Eun-Soon; Gho, Yong Song; Cho, S.-H.; Kim, Y.-Y.; Kim, Y.-K.

doi:10.1111/j.1398-9995.2007.01593.x

Cited by 19 publications

(19 citation statements)

References 25 publications

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Section: Introductionsupporting

confidence: 80%

“…As a consequence, they develop chronic dermatitis with strong similarities to AD [3,4]. Consistent with the mouse data, reduced expression of FGFR1 and FGFR2 was detected in the skin of AD patients [5], and single nucleotide polymorphisms in the FGFR1 and FGFR2 genes were linked to atopy [6].Besides the mechanical barriers, various immune cells, including Langerhans cells [7], conventional αβ T cells, and unconventional γδ T cells [8,9] contribute to skin homeostasis. γδ T cells represent only a small percentage of all T cells in the epidermis (1-10%) and dermis (2-9%) of human skin [10,11].…”

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confidence: 72%

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Accumulation and activation of epidermal γδ T cells in a mouse model of chronic dermatitis is not required for the inflammatory phenotype

et al. 2015

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Chronic skin inflammation resulting from a defective epidermal barrier is a hallmark of atopic dermatitis (AD). We previously demonstrated that mice lacking FGF receptors 1 and 2 in keratinocytes (K5-R1/R2 mice) develop an AD-like chronic dermatitis as a result of an impaired epidermal barrier. Here, we show that γδ T cells, which rapidly respond to various insults, accumulate in the epidermis of K5-R1/R2 mice before the development of histological abnormalities. Their number and activation further increase as the phenotype progresses, most likely as a consequence of increased expression of Il-2 and Il-7 and the stress-induced proteins Rae-1, H60c, Mult1, PlexinB2, and Skint1. To determine the role of γδ T cells in the skin phenotype, we generated quadruple mutant K5-R1/-R2 mice lacking γδ T cells. Surprisingly, loss of γδ T cells did not or only marginally affect keratinocyte proliferation, epidermal thickness, epidermal barrier function, and accumulation and activation of different immune cells in the skin of K5-R1/R2 mice, possibly due to partial compensation by αβ T cells. These results demonstrate that γδ T cells do not contribute to the development or maintenance of chronic inflammation in response to a defect in the epidermal barrier. Keywords: Atopic dermatitis r Barrier function r Dendritic epidermal T cells r Inflammation r T cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe skin is the first line of defense against the environment and protects against excessive water loss and penetration of pathogens, allergens, or irritants. The cornified envelope and the associated lipid bilayer as well as tight junctions are the major components of the epidermal barrier [1]. Their importance is reflected by the findings that genetic or epigenetic alterations in genes encoding protein components of these structures are linked to the development of chronic inflammatory skin diseases, such as atopic dermatitis (AD) [2].Correspondence: Dr. Sabine Werner e-mail: sabine.werner@biol.ethz.ch FGF signaling in keratinocytes plays an important role in the control of epidermal barrier function. Thus, mice lacking FGF receptors (FGFR) 1 and 2 in keratinocytes (K5-R1/R2 mice) show severe transepidermal water loss (TEWL) due to downregulation of tight junction components. As a consequence, they develop chronic dermatitis with strong similarities to AD [3,4]. Consistent with the mouse data, reduced expression of FGFR1 and FGFR2 was detected in the skin of AD patients [5], and single nucleotide polymorphisms in the FGFR1 and FGFR2 genes were linked to atopy [6].Besides the mechanical barriers, various immune cells, including Langerhans cells [7], conventional αβ T cells, and unconventional γδ T cells [8,9] contribute to skin homeostasis. γδ T cells represent only a small percentage of all T cells in the epidermis (1-10%) and dermis (2-9%) of human skin [10,11]. However,www.eji-journal.eu 2518 Jitka Sulcova et al. Eur. J. Immunol. 2015. 45: 2517-25...

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Section: Introductionsupporting

confidence: 80%

supporting

confidence: 72%

Accumulation and activation of epidermal γδ T cells in a mouse model of chronic dermatitis is not required for the inflammatory phenotype

et al. 2015

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“…For example, increased TGF-b1 levels are associated with increased airway remodeling but decreased airways responsiveness in transgenic mice over-expressing TGFB1 in the lungs (42). In humans, TGF-b1 has been shown to stimulate increased synthesis of fibronectin/collagen (26,27), stimulate smooth muscle proliferation in the airways of people with asthma (by increasing both smooth muscle cell size and number) (43), and enhance immune responses against viral illnesses (44).…”

Section: Discussionmentioning

confidence: 99%

Variants in TGFB1, Dust Mite Exposure, and Disease Severity in Children with Asthma

Sharma¹,

Raby²,

Hunninghake³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Polymorphisms in the gene for transforming growth factor-b1 (TGFB1) have been associated with asthma, but not with airway responsiveness or disease exacerbations in subjects with asthma. Objectives: To test for association between single nucleotide polymorphisms (SNPs) in TGFB1 and markers of asthma severity in childhood. Methods: We tested for the association between nine SNPs in TGFB1 and indicators of asthma severity (lung function, airway responsiveness, and disease exacerbations) in two cohorts: 416 Costa Rican parent-child trios and 465 families of non-Hispanic white children in the Childhood Asthma Management Program (CAMP). We also tested for the interaction between these polymorphisms and exposure to dust mite allergen on asthma severity. Measurements and Main Results: The A allele of promoter SNP rs2241712 was associated with increased airway responsiveness in Costa Rica (P 5 0.0006) and CAMP (P 5 0.005), and the C allele of an SNP in the promoter region (rs1800469) was associated with increased airway responsiveness in both cohorts (P < 0.01). Dust mite exposure modified the effect of the C allele of exonic SNP rs1800471 on airway responsiveness (P 5 0.03 for interactions in both cohorts). The T allele of a coding SNP (rs1982073) was associated with a reduced risk of asthma exacerbations in Costa Rica (P 5 0.009) and CAMP (P 5 0.005). Dust mite exposure also significantly modified the effect of the A allele of the promoter SNP rs2241712 on asthma exacerbations in both cohorts. Conclusions: SNPs in TGFB1 are associated with airway responsiveness and disease exacerbations in children with asthma. Moreover, dust mite exposure may modify the effect of TGFB1 SNPs on airway responsiveness and asthma exacerbations.

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“…Consistent with our findings, down-regulation of FGFR1 and FGFR2 expression was detected in the skin of AD patients, 14 and singlenucleotide polymorphisms in the FGFR1 and FGFR2 genes were linked to atopy. 15 Therefore, K5-R1/R2 mice are useful to study the molecular and cellular mechanisms underlying chronic skin inflammation that results from a defective barrier.…”

mentioning

confidence: 99%

Mast Cells Are Dispensable in a Genetic Mouse Model of Chronic Dermatitis

Sulcova

Meyer

Guiducci

et al. 2015

The American Journal of Pathology

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Chronic inflammatory skin diseases, such as atopic dermatitis, affect a large percentage of the population, but the role of different immune cells in the pathogenesis of these disorders is largely unknown. Recently, we found that mice lacking fibroblast growth factor receptor 1 (Fgfr1) and Fgfr2 (K5-R1/R2 mice) in the epidermis have a severe impairment in the epidermal barrier, which leads to the development of a chronic inflammatory skin disease that shares many features with human atopic dermatitis. Using Fgfr1-/Fgfr2-deficient mice, we analyzed the consequences of the loss of mast cells. Mast cells accumulated and degranulated in the skin of young Fgfr1-/Fgfr2-deficient mice, most likely as a consequence of increased expression of the mast cell chemokine Ccl2. The increase in mast cells occurred before the development of histological abnormalities, indicating a functional role of these cells in the inflammatory skin phenotype. To test this hypothesis, we mated the Fgfr1-/Fgfr2-deficient mice with mast cell-deficient CreMaster mice. Surprisingly, loss of mast cells did not or only mildly affect keratinocyte proliferation, epidermal thickness, epidermal barrier function, accumulation and activation of different immune cells, or expression of different proinflammatory cytokines in the skin. These results reveal that mast cells are dispensable for the development of chronic inflammation in response to a defect in the epidermal barrier.

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Distinct association of genetic variations of vascular endothelial growth factor, transforming growth factor‐β, and fibroblast growth factor receptors with atopy and airway hyperresponsiveness

Abstract: The expression of atopy and AHR is distinctly associated with genetic variations in VEGF, TGF-beta1, and FGFR in the Korean population.

Cited by 19 publications

References 25 publications

Accumulation and activation of epidermal γδ T cells in a mouse model of chronic dermatitis is not required for the inflammatory phenotype

Accumulation and activation of epidermal γδ T cells in a mouse model of chronic dermatitis is not required for the inflammatory phenotype

Variants in TGFB1, Dust Mite Exposure, and Disease Severity in Children with Asthma

Mast Cells Are Dispensable in a Genetic Mouse Model of Chronic Dermatitis

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