Dataset Information

Dermatophagoides farinae Extract Induces Interleukin 33-Mediated Atopic Skin Inflammation via Activation of RIP1.

ABSTRACT: Receptor-interacting protein kinase (RIP) family 1 signaling has complex effects on inflammatory processes and cell death, but little is known concerning allergic skin diseases. We examined the role of RIP1 in Dermatophagoides farinae extract (DFE)-induced atopic dermatitis (AD)-like skin inflammation. RIP1 phosphorylation was increased in HKCs treated with DFE. Nectostatin-1, a selective and potent allosteric inhibitor of RIP1, inhibited AD-like skin inflammation and the expression of histamine, total IgE, DFE-specific IgE, IL-4, IL-5, and IL-13 in an AD-like mouse model. The expression of RIP1 was increased in ear skin tissue from a DFE-induced mouse model with AD-like skin lesions and in the lesional skin of AD patients with high house dust mite sensitization. The expression of IL-33 was down-regulated after RIP1 inhibition, and the levels of IL-33 were increased by over-expression of RIP1 in keratinocytes stimulated with DFE. Nectostatin-1 reduced IL-33 expression in vitro and in the DFE-induced mouse model. These results suggest that RIP1 can be one of the mediators that regulate IL-33-mediated atopic skin inflammation by house dust mites.

SUBMITTER: Jin M

PROVIDER: S-EPMC10049056 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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<i>Dermatophagoides farinae</i> Extract Induces Interleukin 33-Mediated Atopic Skin Inflammation via Activation of RIP1.

Jin Meiling M Bang Jin Seon JS Ha Dae-Lyong DL Kim Jun Young JY Park Kyung Duck KD Lee Weon Ju WJ Lee Seok-Jong SJ Choi Jin Kyeong JK Choi Young-Ae YA Jang Yong Hyun YH Kim Sang-Hyun SH

International journal of molecular sciences 20230309 6

Receptor-interacting protein kinase (RIP) family 1 signaling has complex effects on inflammatory processes and cell death, but little is known concerning allergic skin diseases. We examined the role of RIP1 in <i>Dermatophagoides farinae</i> extract (DFE)-induced atopic dermatitis (AD)-like skin inflammation. RIP1 phosphorylation was increased in HKCs treated with DFE. Nectostatin-1, a selective and potent allosteric inhibitor of RIP1, inhibited AD-like skin inflammation and the expression of hi ...[more]

PMID: 36982304

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Project description:House dust mites (HDMs) are a major source of indoor allergens that cause airway allergic disease. Dermatophagoides farinae, a predominant species of HDMs in China, has demonstrated pathogenic role in allergic disorders. Exosomes derived from human bronchoalveolar lavage fluid have been strongly associated with allergic respiratory diseases progression. However, the pathogenic role of D. farinae-derived exosomes in allergic airway inflammation has remained unclear until now. Here, D. farinae was stirred overnight in phosphate-buffered saline, and the supernatant was used to extract exosomes by ultracentrifugation. Then, shotgun liquid chromatography-tandem mass spectrometry and small RNA sequencing were performed to identify proteins and microRNAs contained in D. farinae exosomes. Immunoblotting, Western blotting, and enzyme-linked immunosorbent assay demonstrated the specific immunoreactivity of D. farinae-specific serum IgE antibody against D. farinae exosomes, and D. farinae exosomes were found to induce allergic airway inflammation in a mouse model. In addition, D. farinae exosomes invaded 16-HBE bronchial epithelial cells and NR8383 alveolar macrophages to release the inflammation-related cytokines interleukin-33 (IL-33), thymic stromal lymphopoietin, tumor necrosis factor alpha, and IL-6, and comparative transcriptomic analysis of 16-HBE and NR8383 cells revealed that immune pathways and immune cytokines/chemokines were involved in the sensitization of D. farinae exosomes. Taken together, our data demonstrate that D. farinae exosomes are immunogenic and may induce allergic airway inflammation via bronchial epithelial cells and alveolar macrophages. IMPORTANCE Dermatophagoides farinae, a predominant species of house dust mites in China, has displayed pathogenic role in allergic disorders, and exosomes derived from human bronchoalveolar lavage fluid have been strongly associated with allergic respiratory diseases progression. However, the pathogenic role of D. farinae-derived exosomes in allergic airway inflammation has remained unclear until now. This study, for the first time, extracted exosomes from D. farinae, and sequenced their protein cargo and microRNAs using shotgun liquid chromatography-tandem mass spectrometry and small RNA sequencing. D. farinae-derived exosomes trigger allergen-specific immune responses and present satisfactory immunogenicity, as revealed by immunoblotting, Western blotting, and enzyme-linked immunosorbent assay and may induce allergic airway inflammation via bronchial epithelial cells and alveolar macrophages. Our data provide insights into the mechanisms of allergic airway inflammation caused with D. farinae-derived exosomes and the treatment of house dust mite-induced allergic airway inflammation.

Project description:Application of allergens onto the sublingual epithelium is used to desensitize allergic individuals, a treatment known as sublingual immunotherapy. However, the response of sublingual epithelial cells to house dust mite allergen and potential tolerance-promoting adjuvants such as Toll-like receptor ligands and calcitriol has not been investigated. In order to study this, primary sublingual epithelial cells were isolated from dogs and cultured in vitro. After 24h incubation with Dermatophagoides farinae extract, TLR2 ligands (FSL-1, heat-killed Listeria monocytogenes, Pam3CSK4), a TLR3 ligand (poly I:C), a TLR4 ligand (LPS) and calcitriol (1,25-dihydroxyvitamin D3), viability of the cells was analyzed using an MTT test and their secretion of IL-6, IL-10, CXCL8 and TGF-β1 was measured by ELISA. Additionally, to evaluate its potential effect as an adjuvant, sublingual epithelial cells were incubated with calcitriol in combination with D. farinae extract followed by measurement of CXCL8 secretion. Furthermore, the effect of D. farinae and calcitriol on the transcriptome was assessed by RNA-sequencing. The viability of the sublingual epithelial cells was significantly decreased by poly I:C, but not by the other stimuli. CXCL8 secretion was significantly increased by D. farinae extract and all TLR ligands apart from LPS. Calcitriol significantly decreased CXCL8 secretion and co-administration with D. farinae extract reduced CXCL8 concentrations to levels seen in unstimulated sublingual epithelial cells. Although detectable, TGF-β1 secretion could not be modulated by any of the stimuli. IL-6 and IL-10 could not be detected at the protein nor at the mRNA level. It can be concluded that D. farinae extract and TLR ligands augment the secretion of the pro-inflammatory chemokine CXCL8, which might interfere with sublingual desensitization. On the other hand, CXCL8 secretion was reduced by co-application of calcitriol and D. farinae extract. Calcitriol therefore seems to be a suitable candidate to be used as adjuvant during sublingual immunotherapy.

Project description:There is no established protocol for the development of an experimental canine atopic dermatitis model in laboratory beagles. This study aimed to establish an experimental model that mimics spontaneous canine atopic dermatitis (CAD) clinically, immunologically, and microbiologically, by repeated epicutaneous applications of mite antigens and to describe the entire process including sensitization and provocation in detail for reproducibility. Six intact male laboratory beagle dogs aged 14 months were included in this study. During the sensitization and provocation phase, the house dust mite (HDM) paste consisted of Dermatophagoides farinae (Der f ) and mineral oil, which was applied focally to the 10 × 10 cm area of the right groin as evenly as possible. Further, 120 mg of Der f was applied to each dog twice a week for 12 weeks during the sensitization phase and 25 mg and 120 mg was applied to each dog for the first 2 weeks and subsequent 2 weeks, respectively, during the provocation phase. Thereafter, the applied area was covered with a dressing. Skin lesions including erythema, hyperpigmentation, excoriation, and lichenification were induced and exacerbated gradually through the experimental time course in all six dogs. The canine atopic dermatitis extent and severity index (CADESI) score and transepidermal water loss (TEWL) significantly increased after sensitization and provocation. IL-13 and IL-31 levels increased significantly after provocation as a result of the activation of the T helper-2 (Th2) response. On the contrary, the IL-10 levels decreased significantly after sensitization, which suggested a suppression of Tregs activity. After the completion of provocation, skin microbiome analysis showed that Firmicutes was the most abundant phylum, which indicated bacterial dysbiosis. This study demonstrated that epicutaneous application of HDM in beagle dogs resulted in the elevation of serum HDM-specific IgE levels and clinical atopic scores, a high TEWL, and microbiome dysbiosis resembling spontaneous CAD. These results suggest that this tailored protocol of epicutaneous exposure to Der f may provide support for the development of the experimental CAD model in laboratory beagles.

Dataset Information

Dermatophagoides farinae Extract Induces Interleukin 33-Mediated Atopic Skin Inflammation via Activation of RIP1.

Publications

<i>Dermatophagoides farinae</i> Extract Induces Interleukin 33-Mediated Atopic Skin Inflammation via Activation of RIP1.

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