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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 -
Frontiers in Immunology 2021Desmogleins are involved in cell adhesion conferring structural skin integrity. However, their role in inflammation has been barely studied, and whether desmoglein-4...
Desmogleins are involved in cell adhesion conferring structural skin integrity. However, their role in inflammation has been barely studied, and whether desmoglein-4 modulates psoriasis lesions is completely unknown. In this study, we assessed the impact of desmoglein-4 deficiency on the severity of imiquimod (IMQ)-induced skin inflammation and psoriasiform lesions. To this end, desmoglein-4 Oncins France Colony A (OFA) with Sprague-Dawley (SD) genetic background were used. Additionally, human RNA-Seq datasets from psoriasis (PSO), atopic dermatitis (AD), and a healthy cohort were analyzed to obtain a desmosome gene expression overview. OFA rats displayed an intense skin inflammation while SD showed only mild inflammatory changes after IMQ treatment. We found that IMQ treatment increased CD3 T cells in skin from both OFA and SD, being higher in desmoglein-4-deficient rats. In-depth transcriptomic analysis determined that PSO displayed twofold less DSG4 expression than healthy samples while both, PSO and AD showed more than three-fold change expression of DSG3 and DSC2 genes. Although underlying mechanisms are still unknown, these results suggest that the lack of desmoglein-4 may contribute to immune-mediated skin disease progression, promoting leukocyte recruitment to skin. Although further research is needed, targeting desmoglein-4 could have a potential impact on designing new biomarkers for skin diseases.
Topics: Animals; CD3 Complex; Case-Control Studies; Chemotaxis, Leukocyte; Desmogleins; Disease Models, Animal; Down-Regulation; Female; Humans; Imiquimod; Inflammation Mediators; Psoriasis; Rats, Sprague-Dawley; Rats, Transgenic; Skin; T-Lymphocytes; Rats
PubMed: 33995349
DOI: 10.3389/fimmu.2021.625617 -
Experimental & Molecular Medicine May 20212'-Hydroxycinnamaldehyde (HCA), the active component isolated from the stem bark of Cinnamomum cassia, exerts anticancer effects through multiple mechanisms. We recently...
2'-Hydroxycinnamaldehyde (HCA), the active component isolated from the stem bark of Cinnamomum cassia, exerts anticancer effects through multiple mechanisms. We recently determined that HCA inhibits signal transducer and activator of transcription 3 (STAT3) signaling in prostate cancer cells. Because STAT3 overactivation has been closely associated with the development of psoriasis, a chronic autoimmune skin disease, we examined whether HCA ameliorates skin lesions in an imiquimod-induced psoriasis-like mouse model. The results showed that intraperitoneal administration of HCA alleviated imiquimod-induced psoriasis-like dermatitis, epidermal thickening, dermal infiltration of inflammatory cells, and proinflammatory cytokine production. Mechanistically, HCA inhibited pyruvate kinase isozyme M2 and STAT3 signaling, leading to the suppression of T cell activation, Th17 cell differentiation, and keratinocyte hyperproliferation. These results suggest that HCA may be a new treatment for psoriasis and other STAT3-mediated skin disorders, such as infection, inflammation and carcinogenesis.
Topics: Animals; Biomarkers; Cell Survival; Cinnamates; Cytokines; Disease Management; Disease Models, Animal; Disease Susceptibility; Imiquimod; Mice; Psoriasis; Pyruvate Kinase; STAT3 Transcription Factor; Signal Transduction; T-Lymphocyte Subsets; Th17 Cells
PubMed: 33990689
DOI: 10.1038/s12276-021-00620-z -
Redox Biology Jul 2021Psoriasis is a chronic inflammatory skin disease with no cure. Although the origin of psoriasis and its underlying pathophysiology remain incompletely understood,...
Psoriasis is a chronic inflammatory skin disease with no cure. Although the origin of psoriasis and its underlying pathophysiology remain incompletely understood, inflammation is a central mediator of disease progression. In this regard, electrophilic nitro-fatty acids (NO-FAs) exert potent anti-inflammatory effects in several in vivo murine models of inflammatory diseases, such as chronic kidney disease and cardiovascular disease. To examine the therapeutic potential of NO-FAs on psoriasiform dermatitis, we employed multiple murine models of psoriasis. Our studies demonstrate that oral treatment with nitro oleic acid (OA-NO) has both preventative and therapeutic effects on psoriasiform inflammation. In line with this finding, oral OA-NO downregulated the production of inflammatory cytokines in the skin. In vitro experiments demonstrate that OA-NO decreased both basal IL-6 levels and IL-17A-induced expression of IL-6 in human dermal fibroblasts through the inhibition of NF-κB phosphorylation. Importantly, OA-NO diminished STAT3 phosphorylation and nuclear translocation via nitroalkylation of STAT3, which inhibited keratinocyte proliferation. Overall, our results affirm the critical role of both NF-κB and STAT3 in the incitement of psoriasiform dermatitis and highlight the pharmacologic potential of small molecule nitroalkenes for the treatment of cutaneous inflammatory diseases, such as psoriasis.
Topics: Animals; Dermatitis; Disease Models, Animal; Fatty Acids; Humans; Inflammation; Mice; NF-kappa B; STAT3 Transcription Factor; Skin
PubMed: 33946017
DOI: 10.1016/j.redox.2021.101987 -
Annals of Dermatology Dec 2020Psoriasis is a common chronic inflammatory skin disease. The development of psoriasis is dependent on many intercellular events such as innate immunity and T...
BACKGROUND
Psoriasis is a common chronic inflammatory skin disease. The development of psoriasis is dependent on many intercellular events such as innate immunity and T cell-mediated inflammation. Furthermore, genetic factors are strongly implicated in the pathophysiology of psoriasis. Although a variety of susceptible genes are identified, it is likely that many important genes remain undisclosed.
OBJECTIVE
The aim of this study is to investigate the possible role of lysine demethylase 2A (KDM2A) in the pathophysiology of psoriasis.
METHODS
We examined the expression of KDM2A using a well established imiquimod-induced psoriasiform dermatitis model.
RESULTS
Immunohistochemistry analysis showed that expression of KDM2A was increased in imiquimod-induced psoriasiform dermatitis. Consistent with this result, KDM2A level was markedly increased in the epidermis of psoriatic patient. When keratinocytes were stimulated with TLR3 agonist poly(I:C), KDM2A was increased at both the mRNA and protein levels. Poly(I:C) increased the expression of psoriasis-related cytokines including tumor necrosis factor-α, interleukin-8, and CCL20, and KDM2A inhibitor daminozide enhanced the poly(I:C)-induced cytokine expression. Finally, topical co-application of imiquimod and daminozide exacerbated the imiquimod-induced psoriasiform dermatitis.
CONCLUSION
Together, these results suggest that KDM2A is increased to negatively regulate the inflammatory reaction of epidermal keratinocytes in psoriasis.
PubMed: 33911791
DOI: 10.5021/ad.2020.32.6.481 -
Annals of Dermatology Apr 2020
Psoriasiform Dermatitis Related with T-Cell Immunoreceptor with Immunoglobulin and Immunoreceptor Tyrosine-Based Inhibitory Motif Domains Inhibitor in a Patient with Non-Small-Cell Lung Cancer.
PubMed: 33911733
DOI: 10.5021/ad.2020.32.2.172 -
Cureus Mar 2021Pembrolizumab is an immune checkpoint inhibitor approved for use in many cancer types such as non-small cell lung cancer (NSCLC), metastatic melanoma, head and neck...
Pembrolizumab is an immune checkpoint inhibitor approved for use in many cancer types such as non-small cell lung cancer (NSCLC), metastatic melanoma, head and neck cancers, hepatocellular carcinoma, and renal cell carcinoma. There are many reported cases of patients on immunotherapy who have discontinued treatment due to the development of immune-related adverse effects (irAE). Recognition of the histopathologic patterns of dermatologic toxicities due to immunotherapy will become increasingly important for ensuring appropriate management and optimal patient care. Here, we present a case of a 72-year-old man with metastatic carcinoma of unknown primary origin treated with pembrolizumab who developed an immune-related cutaneous adverse event (ircAE) in the form of lichenoid dermatitis.
PubMed: 33842144
DOI: 10.7759/cureus.13768 -
Acta Dermato-venereologica Mar 2021
Topics: Aged; Drug Eruptions; Exanthema; Female; Humans; Phosphatidylinositol 3-Kinases; Psoriasis
PubMed: 33723614
DOI: 10.2340/00015555-3783 -
The Journal of Dermatology May 2021We report the 5-year follow-up results from a single-arm, open-label, multicenter phase II study (ONO-4538-08) conducted in Japan. Twenty-four patients with...
We report the 5-year follow-up results from a single-arm, open-label, multicenter phase II study (ONO-4538-08) conducted in Japan. Twenty-four patients with treatment-naïve, recurrent, or unresectable stage III/IV malignant melanoma received 3 mg/kg nivolumab every 2 weeks until progressive disease or unacceptable toxicity occurred. The 5-year overall survival (OS) rate was 26.1%. Five years after the start of nivolumab treatment, there were six survivors. The 5-year OS rate was 66.7% for patients with a superficial spreading type, 14.3% for acral lentiginous type, and 16.7% for mucosal type. The 5-year progression-free survival rate was 17.2%. No new cases of partial response or complete response were observed after 3 years, and overall response and disease control rates were similar to those reported at 3 years. The treatment-related adverse events reported between the 3- and 5-year follow-up periods were anemia (grade 2), white blood cell count decrease (grade 2), and psoriasiform dermatitis (grade 2) in one patient each. No new grade 3 or higher treatment-related adverse events occurred in this period. In conclusion, first-line treatment with nivolumab in Japanese patients with unresectable or metastatic melanoma resulted in confirmed long-term survival. No new safety signals were reported in the studied population.
Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Ipilimumab; Japan; Melanoma; Nivolumab; Progression-Free Survival; Skin Neoplasms
PubMed: 33715172
DOI: 10.1111/1346-8138.15804