Abstract:Background
While the incidence of patients with atopic dermatitis (AD) with atopic march (AM) showing respiratory allergy is steadily rising, the pathomechanism is still unknown. There are currently no biomarkers to predict progression of AM.
Methods
To explore the mechanism of AM, patients with AD and AM and healthy controls were recruited and RNA microarray, flow cytometry, quantitative real-time polymerase chain reaction, and immunofluorescence staining were performe… Show more
“…Consistent with previous studies, MPO 36 (myeloperoxidase), FABP5 37 (fatty acid-binding protein 5), CTSG (Cathepsin G), 38 Periostin, 39 14-3-3 protein epsilon, 40 MMP-8 41 and MMP-9, 41 VASP, 42 Galectin-10, 43,44 Pleckstrin (PLEK), 45 Peptidoglycan Recognition Protein 1(PGLYRP1) 46 ,andCCL18 47 were observed to be significantly increased in AD patients compared with HC in our cohort, suggesting the potential role in pro-inflammatory activities of these proteins in the atopic march. Serum LCN2 (neutrophil gelatinase-associated lipocalin) associates with itchiness in skin disease.…”
Background
Atopic dermatitis (AD) is a severe global burden on physical, physiological, and mental health. The role of IL‐37, a fundamental inhibitor of immunity, in AD was herein explored.
Method
Serum levels of IL‐37 and T helper (Th) 2‐related inflammatory mediators were quantified in subjects with or without AD. The expression of IL‐37 receptors was determined by flow cytometry. Proteomics was employed to explore the serum protein profile and novel biomarkers. In vitro cell model, 3D‐keratinocytes mimicking skin model, and the serum of subjects with or without AD were investigated to verify the proteomic results.
Results
AD patients were found to present with higher levels of total and specific IgE as well as Th2 inflammatory mediators compared with healthy controls (HC). IL‐37 level and its receptor IL18Rɑ expression in AD patients were significantly decreased, together with increased population of eosinophils, indicating that the signaling of IL37/IL18Rɑ was dampened. In addition, proteomic analysis revealed a significantly differential protein profile of AD patients compared with HC. IL‐37 showed the strongest negative correlation with involucrin, a keratinizing epithelia protein. IL‐37 was verified to suppress induced involucrin expression in in vitro skin cell models. AD patients show a significantly higher serum concentration of involucrin compared with HC. Together, our results demonstrated that IL‐37 plays a regulatory role in AD. Its deficiency may lead to the aberrant involucrin expression in AD.
Conclusions
The dysregulation of serum protein and skin disruption in AD is related to the insufficiency of IL‐37 and its attenuated anti‐inflammatory signaling.
“…Consistent with previous studies, MPO 36 (myeloperoxidase), FABP5 37 (fatty acid-binding protein 5), CTSG (Cathepsin G), 38 Periostin, 39 14-3-3 protein epsilon, 40 MMP-8 41 and MMP-9, 41 VASP, 42 Galectin-10, 43,44 Pleckstrin (PLEK), 45 Peptidoglycan Recognition Protein 1(PGLYRP1) 46 ,andCCL18 47 were observed to be significantly increased in AD patients compared with HC in our cohort, suggesting the potential role in pro-inflammatory activities of these proteins in the atopic march. Serum LCN2 (neutrophil gelatinase-associated lipocalin) associates with itchiness in skin disease.…”
Background
Atopic dermatitis (AD) is a severe global burden on physical, physiological, and mental health. The role of IL‐37, a fundamental inhibitor of immunity, in AD was herein explored.
Method
Serum levels of IL‐37 and T helper (Th) 2‐related inflammatory mediators were quantified in subjects with or without AD. The expression of IL‐37 receptors was determined by flow cytometry. Proteomics was employed to explore the serum protein profile and novel biomarkers. In vitro cell model, 3D‐keratinocytes mimicking skin model, and the serum of subjects with or without AD were investigated to verify the proteomic results.
Results
AD patients were found to present with higher levels of total and specific IgE as well as Th2 inflammatory mediators compared with healthy controls (HC). IL‐37 level and its receptor IL18Rɑ expression in AD patients were significantly decreased, together with increased population of eosinophils, indicating that the signaling of IL37/IL18Rɑ was dampened. In addition, proteomic analysis revealed a significantly differential protein profile of AD patients compared with HC. IL‐37 showed the strongest negative correlation with involucrin, a keratinizing epithelia protein. IL‐37 was verified to suppress induced involucrin expression in in vitro skin cell models. AD patients show a significantly higher serum concentration of involucrin compared with HC. Together, our results demonstrated that IL‐37 plays a regulatory role in AD. Its deficiency may lead to the aberrant involucrin expression in AD.
Conclusions
The dysregulation of serum protein and skin disruption in AD is related to the insufficiency of IL‐37 and its attenuated anti‐inflammatory signaling.
“…7e ). Of note, Stat4 , Scin and Cytip genes have all been associated with DC activation/migration and Fabp5 gene expression has linked fatty acid metabolism to Th17 differentiation 51 , 52 . Fig.…”
Migratory dendritic cells expressing CD103 are the targets for mucosal vaccines. These belong to either of two lineage-restricted subsets, cDC1 or cDC2 cells, which have been linked to priming of functionally distinct CD4 T cells. However, recent studies have identified plasticity in cDC2 cells with overlapping functions with cDC1 cells, while the converse has not been reported. We genetically engineered a vaccine adjuvant platform that targeted the cholera toxin A1 (CTA1) ADP-ribosylating enzyme to CD103+ cDC1 and cDC2 cells using a single-chain antibody (scFv) to CD103. Unexpectedly, intranasal immunization with the CTA1-svFcCD103 adjuvant modified cDC1 cells to effectively prime Th17 cells, a function previously limited to cDC2 cells. In fact, cDC2 cells were dispensible, while cDC1 cells, lacking in Batf3−/− mice, were critical. Following intranasal immunizations isolated cDC1 cells from mLN exclusively promoted Rorgt+ T cells and IL-17, IL-21, and IL-22 production. Strong CD8 T cell responses through antigen cross presentation by cDC1 cells were also observed. Single-cell RNAseq analysis revealed upregulation of Th17-promoting gene signatures in sorted cDC1 cells. Gene expression in isolated cDC2 cells was largely unaffected. Our finding represents a major shift of paradigm as we have documented functional plasticity in cDC1 cells.
“…PPARδ is upregulated in the epidermis of lesional atopic dermatitis when compared to non-lesional skin but to a lesser extent than in psoriatic lesions [ 31 ]. The expression of FABP5 parallels that of PPARδ in psoriasis and atopic dermatitis [ 31 , 73 ]. Notably, the expression of Ppard and Fabp5 is markedly increased in the epidermis of mouse models of lesional atopic dermatitis [ 38 , 74 ].…”
Section: Ppardelta In Psoriasis and Atopic Dermatitismentioning
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors expressed in the skin. Three PPAR isotypes, α (NRC1C1), β or δ (NRC1C2) and γ (NRC1C3), have been identified. After activation through ligand binding, PPARs heterodimerize with the 9-cis-retinoic acid receptor (RXR), another nuclear hormone receptor, to bind to specific PPAR-responsive elements in regulatory regions of target genes mainly involved in organogenesis, cell proliferation, cell differentiation, inflammation and metabolism of lipids or carbohydrates. Endogenous PPAR ligands are fatty acids and fatty acid metabolites. In past years, much emphasis has been given to PPARα and γ in skin diseases. PPARβ/δ is the least studied PPAR family member in the skin despite its key role in several important pathways regulating inflammation, keratinocyte proliferation and differentiation, metabolism and the oxidative stress response. This review focuses on the role of PPARβ/δ in keratinocytes and its involvement in psoriasis and atopic dermatitis. Moreover, the relevance of targeting PPARβ/δ to alleviate skin inflammation is discussed.
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