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Biomedicine & Pharmacotherapy =... Dec 2021Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia and cellular infiltration. Studies have shown that disease development depends on...
Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia and cellular infiltration. Studies have shown that disease development depends on proinflammatory cytokines, such as interleukin (IL)-23 and IL-17. It has been suggested that IL-23 produced by innate immune cells, such as macrophages, stimulates a subset of helper T cells to release IL-17, promoting neutrophil recruitment and keratinocyte proliferation. However, recent studies have revealed the crucial role of γδT cells in psoriasis pathogenesis as the primary source of dermal IL-17. The nuclear receptors REV-ERBs are ligand-dependent transcription factors recognized as circadian rhythm regulators. REV-ERBs negatively regulate IL-17-producing helper T cells, whereas the involvement of REV-ERBs in regulating IL-17-producing γδT (γδT17) cells remains unclear. Here we revealed the regulatory mechanism involving γδT17 cells through REV-ERBs. γδT17 cell levels were remarkably elevated in the secondary lymphoid organs of mice that lacked an isoform of REV-ERBs. A synthetic REV-ERB agonist, SR9009, suppressed γδT17 cells in vitro and in vivo. Topical application of SR9009 to the skin reduced the inflammatory symptoms of psoriasiform dermatitis in mice. The results of this study provide a novel therapeutic approach for psoriasis targeting REV-ERBs in γδT17 cells.
Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents; Cells, Cultured; Disease Models, Animal; Down-Regulation; Female; Interleukin-17; Intraepithelial Lymphocytes; Mice, Knockout; Nuclear Receptor Subfamily 1, Group D, Member 1; Psoriasis; Pyrrolidines; Signal Transduction; Skin; Thiophenes; Mice
PubMed: 34628169
DOI: 10.1016/j.biopha.2021.112283 -
Clinical, Cosmetic and Investigational... 2021Psoriasis is a common cutaneous disease with multiple characteristics including inflammation and aberrant keratinocyte proliferation. However, the pathogenesis of...
PURPOSE
Psoriasis is a common cutaneous disease with multiple characteristics including inflammation and aberrant keratinocyte proliferation. However, the pathogenesis of psoriasis is not completely clear yet. The objective of this study is to perform an in-depth analysis of the association between SPRR and LCE in the pathogenesis of psoriasis.
METHODS
In this study, we explore the differentially expressed genes (DEGs) in psoriasis by analyzing different gene expression profiles obtained from the Gene Expression Omnibus (GEO) database. The DEGs were examined using gene ontology (GO) functional enrichment analysis and protein-protein interactions (PPI) network. Correlation analysis in R studio software was used to analyze the association between SPRR and LCE genes. Further, potential direct protein-protein interactions between SPRR proteins and LCE3D were verified by co-localization observations and co-immunoprecipitation (CO-IP) assays in 293T cells. Also, the expression levels of SPRR and LCE genes were detected in lesional skin of the IMQ-induced psoriasiform dermatitis mice using RT-PCR.
RESULTS
Interestingly, the small proline-rich (SPRR) and late cornified envelope (LCE) genes were identified as a module in the constructed PPI network. And the analysis of the gene expression profile GSE63684 showed that both SPRR family and LCE family genes were significantly upregulated in imiquimod (IMQ) induced psoriasiform dermatitis mice. Also, the correlation analysis in R studio software recognized the association of SPRR and LCE genes, which were further verified by co-localization and co-immunoprecipitation (CO-IP) assays in 293T cells, and the results show that the direct interactions between SPRR2 and LCE3D. Notably, we also found that the expression levels of SPRR and LCE genes were significantly increased in the IMQ-induced psoriasiform dermatitis mice, while specifically decreased under the tazarotene cream treatment, indicating that the SPRR and LCEs were regulated simultaneously in psoriasis.
CONCLUSION
In summary, our study found that interactions between SPRR proteins and LCE proteins may provide new insights into the pathogenesis of psoriasis.
PubMed: 34594126
DOI: 10.2147/CCID.S336072 -
Frontiers in Immunology 2021Psoriasis is a common inflammatory skin disease resulting from an interplay of keratinocytes and immune cells. Previous studies have identified an essential role of...
Psoriasis is a common inflammatory skin disease resulting from an interplay of keratinocytes and immune cells. Previous studies have identified an essential role of autophagy in the maintenance of epidermal homeostasis including proliferation and differentiation. However, much less is known about the role of autophagy-related proteins in the cutaneous immune response. Herein, we showed that ULK1, the key autophagic initiator, and its phosphorylation at Ser556 were distinctively decreased in the epidermis from lesional skin of psoriasis patients. Topical application of SBI0206965, a selective ULK1 inhibitor, significantly attenuated epidermal hyperplasia, infiltration of neutrophils, and transcripts of the psoriasis-related markers in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD). , ULK1 impairment by siRNA and SBI0206965 arrested cell proliferation and promoted apoptosis of keratinocytes but had a marginal effect on the expression of proinflammatory mediators under steady status. Surprisingly, SBI0206965 blocked the production of chemokines and cytokines in keratinocytes stimulated by neutrophils. Of interest, the pro-apoptotic and anti-inflammatory effects of ULK1 inhibition cannot be fully replicated by autophagic inhibitors. Our findings suggest a self-regulatory process by downregulating ULK1 to maintain the immune homeostasis of psoriatic skin regulating keratinocytes and their crosstalk with neutrophils, possibly through both autophagy-dependent and independent mechanisms. ULK1 might be a potential target for preventing or treating psoriasis.
Topics: Animals; Autophagy; Autophagy-Related Protein-1 Homolog; Biomarkers; Cell Communication; Disease Models, Animal; Disease Susceptibility; Humans; Immunohistochemistry; Keratinocytes; Mice; Molecular Targeted Therapy; Neutrophil Infiltration; Neutrophils; Protein Kinase Inhibitors; Psoriasis
PubMed: 34421918
DOI: 10.3389/fimmu.2021.714274 -
Annals of Dermatology Aug 2021Psoriasis is a chronic inflammatory skin disease. The etiology of psoriasis is not fully understood, but the genetic background is considered to be the most important...
BACKGROUND
Psoriasis is a chronic inflammatory skin disease. The etiology of psoriasis is not fully understood, but the genetic background is considered to be the most important factor. To date, many psoriasis-related genes have been discovered, but the role of many important genes has not been well understood.
OBJECTIVE
The purpose of this study is to uncover possible roles of in psoriasis.
METHODS
Expression of MDA5 was investigated using immunohistochemistry. Then, was overexpressed in keratinocytes using a recombinant adenovirus.
RESULTS
As a result of immunohistochemical staining, the expression of was significantly increased in the epidermis of psoriasis compared to normal skin. Similarly, the expression of was increased in imiquimod-induced psoriasiform dermatitis model. In cultured keratinocytes, toll-like receptor 3 agonist poly(I:C) induced expression of at both mRNA and protein levels. When was overexpressed using a recombinant adenovirus, poly(I:C)-induced cytokine expression was significantly increased. Finally, overexpression significantly inhibited calcium-induced differentiation of keratinocytes.
CONCLUSION
These results suggest that MDA5 increases in psoriasis and negatively regulates keratinocyte differentiation.
PubMed: 34341635
DOI: 10.5021/ad.2021.33.4.339 -
Frontiers in Medicine 2021Superficial perivascular dermatitis, an important type of inflammatory dermatosis, comprises various skin diseases, which are difficult to distinguish by clinical...
Superficial perivascular dermatitis, an important type of inflammatory dermatosis, comprises various skin diseases, which are difficult to distinguish by clinical manifestations and need pathological imaging observation. Coupled with its complex pathological characteristics, the subtype classification depends to a great extent on dermatopathologists. There is an urgent need to develop an efficient approach to recognize the pathological characteristics and classify the subtypes of superficial perivascular dermatitis. 3,954 pathological images (4 × and 10 ×) of three subtypes-psoriasiform, spongiotic and interface-of superficial perivascular dermatitis were captured from 327 cases diagnosed both clinically and pathologically. The control group comprised 1,337 pathological images of 85 normal skin tissue slides taken from the edge of benign epidermal cysts. First, senior dermatologists and dermatopathologists followed the structure-pattern analysis method to label the pathological characteristics that significantly contribute to classifying different subtypes on 4 × and 10 × images. A cascaded deep learning algorithm framework was then proposed to establish pixel-level pathological characteristics' masks and classify the subtypes by supervised learning. 13 different pathological characteristics were recognized, and the accuracy of subtype classification was 85.24%. In contrast, the accuracy of the subtype classification model without recognition was 71.35%. Our cascaded deep learning model used small samples to deliver efficient recognition of pathological characteristics and subtype classification simultaneously. Moreover, the proposed method could be applied to both microscopic images and digital scanned images.
PubMed: 34336900
DOI: 10.3389/fmed.2021.696305 -
Biomedicine & Pharmacotherapy =... Sep 2021Psoriasis is one of the most common chronic inflammatory diseases that is characterized by well-defined erythematous plaques, with typical histopathological findings of...
Psoriasis is one of the most common chronic inflammatory diseases that is characterized by well-defined erythematous plaques, with typical histopathological findings of lymphocytic infiltration and epidermal hyperplasia. Topical treatments of psoriasis are either associated with limited response or with side effects. Up to date, topicals targeting neuroimmune axis in psoriasis or psoriasiform dermatitis have not been explored. Here, we investigated whether percutaneous delivery of capsaicin could attenuate the pathological change of psoriasiform inflammation. Imiquimod-induced psoriasis-like murine model was used to evaluate therapeutic effects from topical application of capsaicin. An additional model of psoriasiform dermatitis induced by direct IL-23 injection was used to identify the level of action from capsaicin in this neuroimmune axis. Cutaneous inflammation was assessed by erythema level and ear thickness change. Key cytokines, infiltrating cells in the skin, and draining lymph node cells were investigated. The results showed that capsaicin administration obstructed the activation of IL-23/IL-17 pathway induced by imiquimod, presenting with significantly reduced psoriasiform dermatitis both in gross appearance and microscopic features. Tissue gene expression of psoriatic core cytokines induced by imiquimod (including IL-23, IL-17A, IL-22, TNF-α, and IL-6) were greatly decreased by capsaicin application. This protective effect from capsaicin could be hampered by direct intradermal injection of IL-23. CONCLUSION: Epicutaneous delivery of capsaicin on imiquimod-treated murine skin could significantly decrease expression of multiple inflammatory cytokines and the severity of prototypic change of psoriasiform inflammation. The beneficial effect imposed by capsaicin reinforces the neuroimmune contribution towards psoriasiform inflammation and provides a potential non-steroidal therapeutic alternative for topical treatment of psoriasiform dermatitis.
Topics: Administration, Topical; Animals; Antineoplastic Agents; Antipruritics; Capsaicin; Dermatitis; Disease Models, Animal; Epidermis; Female; Hyperplasia; Imiquimod; Mice; Mice, Inbred BALB C; Psoriasis; Skin
PubMed: 34328106
DOI: 10.1016/j.biopha.2021.111950 -
International Journal of Molecular... Jul 2021We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other... (Review)
Review
We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis-e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey-Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)-vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor).
Topics: Animals; Antigens, CD34; Dermatitis; Dermis; Humans; Neoplasm Proteins; Skin Neoplasms; Telocytes
PubMed: 34298962
DOI: 10.3390/ijms22147342 -
Allergy Mar 2022Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth...
BACKGROUND
Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations.
METHODS
The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cT ) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape.
RESULTS
Mean age at disease onset was 38 ± 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4 T cells, Treg, and cT cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years).
CONCLUSION
This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.
Topics: Humans; Inflammatory Bowel Diseases; Microfilament Proteins; Mutation; Phenotype; Primary Immunodeficiency Diseases
PubMed: 34287962
DOI: 10.1111/all.15010 -
Nature Communications Jul 2021CCCH zinc finger proteins resolve immune responses by degrading the mRNAs of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6. Here we...
CCCH zinc finger proteins resolve immune responses by degrading the mRNAs of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6. Here we report that one such family member, monocyte chemotactic protein-induced protein 3 (MCPIP3, also named ZC3H12C or Regnase-3), promotes skin inflammation by simultaneously enhancing TNF in macrophages and repressing IL-6 in plasmacytoid dendritic cells (pDCs). MCPIP3 is positively associated with psoriasis pathogenesis, and highly expressed by macrophages and pDCs. MCPIP3-deficient macrophages produce less TNF and IL-12p40. However, MCPIP3-deficient pDCs secrete significantly more IL-6. This enhanced intradermal IL-6 may alleviate imiquimod-induced skin inflammation. As a result, MCPIP3-deficient mice are protected from imiquimod-induced psoriasiform lesions. Furthermore, early exposure to pDC-derived IL-6 suppresses macrophage-derived TNF and IL-12p40. Mechanistically, MCPIP3 could directly degrade mRNAs of IL-6, Regnase-1, and IκBζ. In turn, Regnase-1 could degrade MCPIP3 mRNAs. Our study identifies a critical post-transcriptional mechanism that synchronizes myeloid cytokine secretion to initiate autoimmune skin inflammation.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Cycle Proteins; Chemokine CCL2; Cytokines; Dendritic Cells; Dermatitis; Endoribonucleases; Epigenomics; Humans; Imiquimod; Inflammation; Interleukin-6; Macrophages; Mice; Mice, Knockout; Myeloid Cells; Psoriasis; Ribonucleases; Skin; Tumor Necrosis Factor-alpha
PubMed: 34215755
DOI: 10.1038/s41467-021-24352-w -
Scientific Reports May 2021Atopic dermatitis (AD) often presents more severely in African Americans (AAs) and with greater involvement of extensor areas. To investigate immune signatures of AD in...
Atopic dermatitis (AD) often presents more severely in African Americans (AAs) and with greater involvement of extensor areas. To investigate immune signatures of AD in AAs with moderate to severe pruritus, lesional and non-lesional punch biopsies were taken from AA patients along with age-, race-, and sex-matched controls. Histology of lesional skin showed psoriasiform dermatitis and spongiotic dermatitis, suggesting both Th2 and Th17 activity. Gene Set Variation Analysis showed upregulation of Th2 and Th17 pathways in both lesional versus non-lesional and lesional versus control (p < 0.01), while Th1 and Th22 upregulation were observed in lesional versus control (p < 0.05). Evidence for a broad immune signature also was supported by upregulated Th1 and Th22 pathways, and clinically may represent greater severity of AD in AA. Furthermore, population-level analysis of data from TriNetX, a global federated health research network, revealed that AA AD patients had higher values for CRP, ferritin, and blood eosinophils compared to age-, sex-, and race-matched controls as well as white AD patients, suggesting broad systemic inflammation. Therefore, AA AD patients may feature broader immune activation than previously thought and may derive benefit from systemic immunomodulating therapies that modulate key drivers of multiple immune pathways.
Topics: Adult; Black or African American; Aged; Case-Control Studies; Cross-Sectional Studies; Dermatitis, Atopic; Female; Humans; Male; Middle Aged; Skin; Th17 Cells; Th2 Cells; Transcriptome
PubMed: 34045476
DOI: 10.1038/s41598-021-90105-w