Periostin is induced by IL-4/IL-13 in dermal fibroblasts and promotes RhoA/ROCK pathway-mediated TGF-β1 secretion in abnormal scar formation

Maeda, Daisuke; Kubo, Tateki; Kiya, Koichiro; Kawai, Kenichiro; Matsuzaki, Shinsuke; Kobayashi, Daichi; Fujiwara, Toshihiro; Katayama, Taiichi; Hosokawa, Ko

doi:10.1080/2000656x.2019.1612752

Cited by 51 publications

(48 citation statements)

References 33 publications

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“…59 The cross talk between fibroblasts and DCs in AD is supported by the lesional skin enrichment of mature (LAMP3 1 ) DCs expressing CCR7, the receptor for CCL19, and type 2 chemokines CCL17 and CCL22, suggesting that FBs interact with macrophages and DCs to facilitate T-cell trafficking, lymphoid tissue organization, and type 2 cell recruitment. These FBs also express POSTN and TNC, which encode ECM proteins that are induced by the defining and profibrotic type 2 cytokines IL4 and IL13, 60,61 which are upregulated in AD, 28,62 and may further propagate type 2 inflammation and fibrotic remodeling in a vicious inflammatory cycle. These FBs may also play a role in fibrotic skin conditions that also have an inflammatory (type 2) component (eg, scleroderma, keloids).…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis

Suryawanshi

Morozov

et al. 2020

Journal of Allergy and Clinical Immunology

338

351

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Background: Atopic dermatitis (AD) is a prevalent inflammatory skin disease with a complex pathogenesis involving immune cell and epidermal abnormalities. Despite whole tissue biopsy studies that have advanced the mechanistic understanding of AD, single cell-based molecular alterations are largely unknown. Objective: Our aims were to construct a detailed, high-resolution atlas of cell populations and assess variability in cell composition and cell-specific gene expression in the skin of patients with AD versus in controls. Methods: We performed single-cell RNA sequencing on skin biopsy specimens from 5 patients with AD (4 lesional samples and 5 nonlesional samples) and 7 healthy control subjects, using 103 Genomics. Results: We created transcriptomic profiles for 39,042 AD (lesional and nonlesional) and healthy skin cells. Fibroblasts demonstrated a novel COL6A5 1 COL18A1 1 subpopulation that was unique to lesional AD and expressed CCL2 and CCL19 cytokines. A corresponding LAMP3 1 dendritic cell (DC) population that expressed the CCL19 receptor CCR7 was also unique to AD lesions, illustrating a potential role for fibroblast signaling to immune cells. The lesional AD samples were characterized by expansion of inflammatory DCs (CD1A 1 FCER1A 1) and tissue-resident memory T cells (CD69 1 CD103 1). The frequencies of type 2 (IL13 1)/type 22 (IL22 1) T cells were higher than those of type 1 (IFNG 1) in lesional AD, whereas this ratio was slightly diminished in nonlesional AD and further diminished in controls. Conclusion: AD lesions were characterized by expanded type 2/type 22 T cells and inflammatory DCs, and by a unique inflammatory fibroblast that may interact with immune cells to regulate lymphoid cell organization and type 2 inflammation.

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Section: Discussionmentioning

confidence: 99%

Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis

Suryawanshi

Morozov

et al. 2020

Journal of Allergy and Clinical Immunology

338

351

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“…In the present study, we observed a significant Th2 signature in keloids as well as increased cellular infiltrates associated with the Th2 microenvironment, such as tryptase + mast cells (12,49,50), markers of dendritic cells characteristic to atopic dermatitis (AD) (OX40L + and FCeR1 + ) (33,47,48), IL-4Ra + cells, and periostin + cells. In human fibroblasts, it has been found that IL-4 and IL-13 increased TGF-b signaling and enhanced fibrosis via periostin (59). Periostin is a matricellular protein that plays important physiologic and pathogenic roles in skin fibrosis (60,61) and serves as a biomarker for several known Th2-associated diseases (e.g.…”

Section: Discussionmentioning

confidence: 99%

RNA Sequencing Keloid Transcriptome Associates Keloids With Th2, Th1, Th17/Th22, and JAK3-Skewing

Duca

Espino

et al. 2020

Front. Immunol.

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Keloids are disfiguring, fibroproliferative growths and their pathogenesis remains unclear, inhibiting therapeutic development. Available treatment options have limited efficacy and harbor safety concerns. Thus, there is a great need to clarify keloid pathomechanisms that may lead to novel treatments. In this study, we aimed to elucidate the profile of lesional and non-lesional keloid skin compared to normal skin. We performed gene (RNAseq, qRT-PCR) and protein (immunohistochemistry) expression analyses on biopsy specimens obtained from lesional and non-lesional skin of African American (AA) keloid patients compared to healthy skin from AA controls. Fold-change≥2 and false-discovery rate (FDR)<0.05 was used to define significance. We found that lesional versus normal skin showed significant up-regulation of markers of T-cell activation/migration (ICOS, CCR7), Th2- (IL-4R, CCL11, TNFSF4/OX40L), Th1- (CXCL9/CXCL10/CXCL11), Th17/Th22- (CCL20, S100As) pathways, and JAK/STAT-signaling (JAK3) (false-discovery rate [FDR]<0.05). Non-lesional skin also exhibited similar trends. We observed increased cellular infiltrates in keloid tissues, including T-cells, dendritic cells, mast cells, as well as greater IL-4rα+, CCR9+, and periostin+ immunostaining. In sum, comprehensive molecular profiling demonstrated that both lesional and non-lesional skin show significant immune alternations, and particularly Th2 and JAK3 expression. This advocates for the investigation of novel treatments targeting the Th2 axis and/or JAK/STAT-signaling in keloid patients.

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“…Periostin is not only highly expressed in healing wounds but is also involved in angiogenesis, a prominent feature of keloids and most likely in all fibrotic diseases. [21][22][23][24] A number of fibroblastic cells can be noted to be embedded into the collagenous matrix (see Figure 1), often with myofibroblastic characteristics with defined expression of marker proteins, specifically α-SMA and vimentin. These cells also prominently display rough endoplasmic reticulum and Golgi apparatus, suggesting their activated synthetic and secretory capacity.…”

Section: Clini C Al and G Ene Tic Fe Ature S Of Keloidsmentioning

confidence: 99%

Keloid disorder: Fibroblast differentiation and gene expression profile in fibrotic skin diseases

Macarak

Wermuth

Rosenbloom

et al. 2020

Experimental Dermatology

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Keloid disorder, a group of fibroproliferative skin diseases, is characterized by unremitting accumulation of the extracellular matrix (ECM) of connective tissue, primarily collagen, to develop cutaneous tumors on the predilection sites of skin. There is a strong genetic predisposition for keloid formation, and individuals of African and Asian ancestry are particularly prone. The principal cell type responsible for ECM accumulation is the myofibroblast derived from quiescent resident skin fibroblasts either through trans-differentiation or from keloid progenitor stem cells with capacity for multi-lineage differentiation and self-renewal. The biosynthetic pathways leading to ECM accumulation are activated by several cytokines, but particularly by TGF-β signalling. The mechanical properties of the cellular microenvironment also play a critical role in the cell's response to TGF-β, as demonstrated by culturing of fibroblasts derived from keloids and control skin on substrata with different degrees of stiffness. These studies also demonstrated that culturing of fibroblasts on tissue culture plastic in vitro does not reflect their biosynthetic capacity in vivo. Collectively, our current understanding of the pathogenesis of keloids suggests a complex network of interacting cellular, molecular and mechanical factors, with distinct pathways leading to myofibroblast differentiation and activation. Keloids can serve as a model system of fibrotic diseases, a group of currently intractable disorders, and deciphering of the critical pathogenetic steps leading to ECM accumulation is expected to identify targets for pharmacologic intervention, not only for keloids but also for a number of other, both genetic and acquired, fibrotic diseases.

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Periostin is induced by IL-4/IL-13 in dermal fibroblasts and promotes RhoA/ROCK pathway-mediated TGF-β1 secretion in abnormal scar formation

Cited by 51 publications

References 33 publications

Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis

Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis

RNA Sequencing Keloid Transcriptome Associates Keloids With Th2, Th1, Th17/Th22, and JAK3-Skewing

Keloid disorder: Fibroblast differentiation and gene expression profile in fibrotic skin diseases

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