Toll-like receptor family members in skin fibroblasts are functional and have a higher expression compared to skin keratinocytes

Cheng, Yong; Oh, Joo Youn; Lee, Dong Hun; Bae, Jung Soo; Jin, Cheng; Park, Chi Hyun; Chung, Jin Ho

doi:10.3892/ijmm.2015.2146

Cited by 77 publications

(54 citation statements)

References 35 publications

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“…Moreover, polymorphisms in TLR2 are reported to be associated with the severity of AD and function of TLR2 is downregulated in AD skin . Furthermore, lipoproteins of S. aureus are known to induce IL‐6 production in keratinocytes via the TLR1/TLR2 pathway . On the other hand, TLR9 is typically located within endosomes and lysosomes, and recognizes CpG DNA of bacteria .…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL‐1α secretion via TLR9

Moriwaki

Iwamoto

Niitsu

et al. 2018

Allergy

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Background: Staphylococcus aureus (S. aureus) is frequently detected in the skin of patients with atopic dermatitis (AD), and involved in the flare of AD. There are some evidence-specific strains of S. aureus affect the severity of AD. However, the mechanism of predominant colonization and the aggravation of dermatitis by certain strains of S. aureus in the patients with AD are still unknown.Objective: To reveal the characteristics of S. aureus from patients with AD (S. aureus-AD), we analyzed the interaction of S. aureus-AD and keratinocytes in comparison with those of S. aureus laboratory strains (S. aureus-stand.). Methods:We stimulated HaCaT cells, keratinocyte cell line, and human epidermal keratinocytes by heat-killed S. aureus strains, then evaluated immune response of keratinocytes by ELISA, immunofluorescence staining, and flow cytometry.Results: Upon incubation with keratinocytes, three out of four strains of heat-killed S. aureus-AD were strongly agglutinated inside the cytoplasm. In the cells, they are located in lysosomes and promoted the secretion of interleukin-1α (IL-1α). These reactions were not observed by any of four strains of S. aureus-stand. and S. epidermidis and were abolished by the treatment of S. aureus with proteinase K. Moreover, the IL-1α secretion was diminished by the inhibition of Toll-like receptor 9 (TLR9). Conclusion: S. aureus-AD accumulates in lysosome of keratinocytes by means of bacterial cell wall proteins and induces IL-1α via TLR9. K E Y W O R D S atopic dermatitis, dermatology, innate immunity, microbiome, staphylococcus aureus 1 | INTRODUCTION Atopic dermatitis (AD) is a common chronic skin disease characterized by pruritus and recurrent eczematous lesions. 1 There is a strong correlation between filaggrin (FLG) mutations and AD, but not all carriers of FLG mutation develop AD, 2 suggesting the involvement of other causative or aggravating factors in the pathogenesis of AD. Many patients with AD frequently suffer from cutaneous infections by Staphylococcus aureus (S. aureus). Moreover, S. aureus is commonly isolated from patients with AD, even from apparently non-lesion skin. 3 Furthermore, S. aureus colonization has been shown to be associated with AD severity and observed even before the onset of AD in infants. 4 A previous study of the skin microbiome of patients with AD revealed reduced diversity and high Staphylococcus proportions in flares of untreated AD, 5 whereas Staphylococcus epidermidis (S. epidermidis) predominates on the skin surface of healthy individuals. In murine models, S. aureus colonization and low diversity of the microbiome drive AD-like lesions in the skin. 6Compared to standard S. aureus strains, S. aureus isolated from AD skin are able to induce different innate immune responses. S. aureus from AD skin are internalized into keratinocytes and accumulate in lysosomes with inducing IL-1α secretion via TLR9. Specific surface proteins of S. aureus from AD skin are responsible for their internalization.

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Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL‐1α secretion via TLR9

Moriwaki

Iwamoto

Niitsu

et al. 2018

Allergy

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“…Whereas TLR3, TLR7, TLR8, TLR9 and TLR13 are localized primarily within endolysosomes and recognizes nucleic acids [35], the rest of the TLR family proteins are present on the cell surface and they largely recognize microbial membrane components. TLRs are also expressed on various immune cells, including T and B cells [36, 37], dendritic cells (DCs) [38], macrophages [39] as well as some non-immune cells such as fibroblasts and epithelial cells [40]. Upon encounter with specific microbial molecules TLR receptor are activated and initiate downstream signaling via MyD88-dependent or -independent pathways [41].…”

Section: Gp96 Cancer-associated Clientelementioning

confidence: 99%

Clients and Oncogenic Roles of Molecular Chaperone gp96/grp94

Ansa-Addo¹,

Thaxton²,

Hong³

et al. 2016

CTMC

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As an endoplasmic reticulum heat shock protein (HSP) 90 paralogue, glycoprotein (gp) 96 possesses immunological properties by chaperoning antigenic peptides for activation of T cells. Genetic studies in the last decade have unveiled that gp96 is also an essential master chaperone for multiple receptors and secreting proteins including Toll-like receptors (TLRs), integrins, the Wnt co-receptor, Low Density Lipoprotein Receptor-Related Protein 6 (LRP6), the latent TGFβ docking receptor, Glycoprotein A Repetitions Predominant (GARP), Glycoprotein (GP) Ib and insulin-like growth factors (IGF). Clinically, elevated expression of gp96 in a variety of cancers correlates with the advanced stage and poor survival of cancer patients. Recent preclinical studies have also uncovered that gp96 expression is closely linked to cancer progression in multiple myeloma, hepatocellular carcinoma, breast cancer and inflammation-associated colon cancer. Thus, gp96 is an attractive therapeutic target for cancer treatment. The chaperone function of gp96 depends on its ATPase domain, which is structurally distinct from other HSP90 members, and thus favors the design of highly selective gp96-targeted inhibitors against cancer. We herein discuss the strategically important oncogenic clients of gp96 and their underlying biology. The roles of cell-intrinsic gp96 in T cell biology are also discussed, in part because it offers another opportunity of cancer therapy by manipulating levels of gp96 in T cells to enhance host immune defense.

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“…1A). Next, in order to investigate whether other PAMPs or PAMP mimics can also inhibit procollagen expression levels in skin fibroblasts, skin fibroblasts were treated with a bacterial PAMP mimic, Pam3CSK4, which is commonly used as a ligand for TLR1/2 (16,20). It was observed that treatment with 5 µg/ml Pam3CSK4 and 20 µg/ml poly(I:C) induced MMP-1 expression to a similar level.…”

Section: Resultsmentioning

confidence: 99%

IRF3 signaling pathway serves an important role in poly(I:C)-induced procollagen reduction in human skin fibroblasts

et al. 2017

Self Cite

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Pattern recognition receptors (PRRs) are part of the immune system. They can recognize pathogen‑associated molecular patterns (PAMPs). Toll‑like receptors (TLRs) and retinoic acid‑inducible gene 1 (RIG‑1)‑like receptors (RLRs) are 2 types of PRR in the innate immune system. Double‑stranded RNA (dsRNA) can exist as a PAMP, including dsRNA viruses. dsRNA is known as a ligand not only for TLR3 but also for RLRs, including melanoma differentiation‑associated gene 5 and RIG‑1. Collagen is the main structural protein in the extracellular space in the skin. Recently, it was reported that treatment of a synthetic dsRNA, poly(I:C), decreases procollagen expression in skin fibroblasts. However, signaling pathways involved in this process have not yet been fully elucidated. The present study further explored the underlying signaling pathways involved in the processes. It was demonstrated by western blotting that treatment of poly(I:C), but not another PAMP, Pam3CSK4, inhibited procollagen expression in cultured human skin fibroblasts. Treatment of poly(I:C)and Pam3CSK4 induced activation of the mitogen‑activated protein kinases and the nuclear factor‑κB pathways. However, only poly(I:C), but not Pam3CSK4, induced the activation of the interferon regulatory factor 3 (IRF3) pathway. By using specific inhibitors, it was demonstrated that inhibition of IRF3 pathway relieved poly(I:C)‑induced procollagen reduction. In conclusion, IRF3 signaling pathway serves an important role in poly(I:C)‑induced procollagen reduction in skin fibroblasts. This suggests that the IRF3 signaling pathway may be a key target for collagen regulation in the skin.

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Toll-like receptor family members in skin fibroblasts are functional and have a higher expression compared to skin keratinocytes

Cited by 77 publications

References 35 publications

Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL‐1α secretion via TLR9

Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL‐1α secretion via TLR9

Clients and Oncogenic Roles of Molecular Chaperone gp96/grp94

IRF3 signaling pathway serves an important role in poly(I:C)-induced procollagen reduction in human skin fibroblasts

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