A role of IL-25, a sibling of IL-17, in triggering psoriatic skin inflammation

The interleukin (IL)-1 family members IL-1α, -1β, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5−/− pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders.

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TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1

eLife ◽

10.7554/elife.10592 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 39

Author(s):

Nima Etemadi ◽

Michael Chopin ◽

Holly Anderton ◽

Maria C Tanzer ◽

James A Rickard ◽

...

Keyword(s):

E3 Ligase ◽

Adaptive Immune System ◽

Sphingosine Kinase ◽

Skin Inflammation ◽

Psoriatic Skin ◽

Sphingosine Kinase 1 ◽

Ubiquitin E3 Ligase ◽

Tnf Superfamily ◽

Sphingosine 1 Phosphate

TRAF2 is a component of TNF superfamily signalling complexes and plays an essential role in the regulation and homeostasis of immune cells. TRAF2 deficient mice die around birth, therefore its role in adult tissues is not well-explored. Furthermore, the role of the TRAF2 RING is controversial. It has been claimed that the atypical TRAF2 RING cannot function as a ubiquitin E3 ligase but counterclaimed that TRAF2 RING requires a co-factor, sphingosine-1-phosphate, that is generated by the enzyme sphingosine kinase 1, to function as an E3 ligase. Keratinocyte-specific deletion of Traf2, but not Sphk1 deficiency, disrupted TNF mediated NF-κB and MAP kinase signalling and caused epidermal hyperplasia and psoriatic skin inflammation. This inflammation was driven by TNF, cell death, non-canonical NF-κB and the adaptive immune system, and might therefore represent a clinically relevant model of psoriasis. TRAF2 therefore has essential tissue specific functions that do not overlap with those of Sphk1.

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Myeloperoxidase Inhibition Ameliorates Plaque Psoriasis in Mice

Antioxidants ◽

10.3390/antiox10091338 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1338

Author(s):

Savannah D. Neu ◽

Anna Strzepa ◽

Dustin Martin ◽

Mary G. Sorci-Thomas ◽

Kirkwood A. Pritchard, Jr. ◽

...

Keyword(s):

Oxidative Damage ◽

Plaque Psoriasis ◽

Skin Inflammation ◽

Skin Lesions ◽

Autoimmune Response ◽

Psoriatic Skin ◽

Imiquimod Cream ◽

Current Therapies ◽

Study Support

Plaque psoriasis is a common inflammatory condition of the skin characterized by red, flaking lesions. Current therapies for plaque psoriasis target many facets of the autoimmune response, but there is an incomplete understanding of how oxidative damage produced by enzymes such as myeloperoxidase contributes to skin pathology. In this study, we used the Aldara (Imiquimod) cream model of plaque psoriasis in mice to assess myeloperoxidase inhibition for treating psoriatic skin lesions. To assess skin inflammation severity, an innovative mouse psoriasis scoring system was developed. We found that myeloperoxidase inhibition ameliorated psoriasis severity when administered either systemically or topically. The findings of this study support the role of oxidative damage in plaque psoriasis pathology and present potential new therapeutic avenues for further exploration.

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Gene expression profiling defines the role of ATP-exposed keratinocytes in skin inflammation

Journal of Dermatological Science ◽

10.1016/j.jdermsci.2010.02.007 ◽

2010 ◽

Vol 58 (2) ◽

pp. 143-151 ◽

Cited By ~ 12

Author(s):

Hiroshi Ohara ◽

Rumiko Saito ◽

Satoshi Hirakawa ◽

Miki Shimada ◽

Nariyasu Mano ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Skin Inflammation

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Zdhhc2 Is Essential for Plasmacytoid Dendritic Cells Mediated Inflammatory Response in Psoriasis

Frontiers in Immunology ◽

10.3389/fimmu.2020.607442 ◽

2021 ◽

Vol 11 ◽

Author(s):

Binhui Zhou ◽

Wenyi Yang ◽

Wushan Li ◽

Le He ◽

Liaoxun Lu ◽

...

Keyword(s):

Inflammatory Response ◽

Plasmacytoid Dendritic Cell ◽

White Blood Cells ◽

Psoriatic Skin ◽

Interferon Α ◽

Inflammatory Disorder ◽

Post Translational Modification ◽

Cellular Components ◽

Deficient Mice

Zdhhc family genes are composed of 24 members that regulate palmitoylation, a post-translational modification process for proteins. Mutations in genes that alter palmitoylation or de-palmitoylation could result in neurodegenerative diseases and inflammatory disorders. In this study, we found that Zdhhc2 was robustly induced in psoriatic skin and loss of Zdhhc2 in mice by CRISPR/Cas9 dramatically inhibited pathology of the ear skin following imiquimod treatment. As psoriasis is an inflammatory disorder, we analyzed tissue infiltrating immune cells and cytokine production. Strikingly we found that a master psoriatic cytokine interferon-α (IFN-α) in the lesioned skin of wildtype (WT) mice was 23-fold higher than that in Zdhhc2 deficient counterparts. In addition, we found that CD45+ white blood cells (WBC) infiltrating in the skin of Zdhhc2 deficient mice were also significantly reduced. Amelioration in psoriasis and dramatically reduced inflammation of Zdhhc2 deficient mice led us to analyze the cellular components that were affected by loss of Zdhhc2. We found that imiquimod induced plasmacytoid dendritic cell (pDC) accumulation in psoriatic skin, spleen, and draining lymph nodes (DLN) were drastically decreased in Zdhhc2 deficient mice, and the expression of pDC activation marker CD80 also exhibited significantly inhibited in psoriatic skin. In further experiments, we confirmed the cell intrinsic effect of Zdhhc2 on pDCs as we found that loss of zDHHC2 in human CAL-1 pDC dampened both interferon regulatory factor 7 (IRF7) phosphorylation and IFN-α production. Therefore, we identified novel function of Zdhhc2 in controlling inflammatory response in psoriasis in mice and we also confirmed that crucial role of Zdhhc2 in pDCs by regulating IRF7 activity and production of the critical cytokine. Our results finding the dependence of IFN-α production on Zdhhc2 in inflamed murine skin and in human pDCs provide rationale for targeting this new molecule in treatment of inflammation.

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Complement component 3 prevents imiquimod-induced psoriatic skin inflammation by inhibiting apoptosis in mice

International Immunopharmacology ◽

10.1016/j.intimp.2020.106692 ◽

2020 ◽

Vol 85 ◽

pp. 106692

Author(s):

Quan-you Zheng ◽

Shen-ju Liang ◽

Feng Xu ◽

Yi Yang ◽

Jian-li Feng ◽

...

Keyword(s):

Skin Inflammation ◽

Complement Component ◽

Psoriatic Skin ◽

Complement Component 3

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Psoriatic skin inflammation induces a pre-diabetic phenotype via the endocrine actions of skin secretome

Molecular Metabolism ◽

10.1016/j.molmet.2020.101047 ◽

2020 ◽

Vol 41 ◽

pp. 101047

Author(s):

Elizabeth A. Evans ◽

Sophie R. Sayers ◽

Xenia Kodji ◽

Yue Xia ◽

Mahum Shaikh ◽

...

Keyword(s):

Skin Inflammation ◽

Psoriatic Skin

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Expression of leukotriene B4 receptor 1 defines functionally distinct DCs that control allergic skin inflammation

Cellular and Molecular Immunology ◽

10.1038/s41423-020-00559-7 ◽

2020 ◽

Author(s):

Tomoaki Koga ◽

Fumiyuki Sasaki ◽

Kazuko Saeki ◽

Soken Tsuchiya ◽

Toshiaki Okuno ◽

...

Keyword(s):

Skin Inflammation ◽

Leukotriene B4 ◽

Conditional Knockout ◽

Activated T Cells ◽

Spatiotemporal Regulation ◽

Allergic Skin ◽

Allergic Contact ◽

Leukotriene B4 Receptor ◽

G Protein Coupled

Abstract Leukotriene B4 (LTB4) receptor 1 (BLT1) is a chemotactic G protein-coupled receptor expressed by leukocytes, such as granulocytes, macrophages, and activated T cells. Although there is growing evidence that BLT1 plays crucial roles in immune responses, its role in dendritic cells remains largely unknown. Here, we identified novel DC subsets defined by the expression of BLT1, namely, BLT1hi and BLT1lo DCs. We also found that BLT1hi and BLT1lo DCs differentially migrated toward LTB4 and CCL21, a lymph node-homing chemoattractant, respectively. By generating LTB4-producing enzyme LTA4H knockout mice and CD11c promoter-driven Cre recombinase-expressing BLT1 conditional knockout (BLT1 cKO) mice, we showed that the migration of BLT1hi DCs exacerbated allergic contact dermatitis. Comprehensive transcriptome analysis revealed that BLT1hi DCs preferentially induced Th1 differentiation by upregulating IL-12p35 expression, whereas BLT1lo DCs accelerated T cell proliferation by producing IL-2. Collectively, the data reveal an unexpected role for BLT1 as a novel DC subset marker and provide novel insights into the role of the LTB4-BLT1 axis in the spatiotemporal regulation of distinct DC subsets.

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Leptin System in Obese Dog Skin: A Pilot Study

Animals ◽

10.3390/ani10122338 ◽

2020 ◽

Vol 10 (12) ◽

pp. 2338

Author(s):

Margherita Maranesi ◽

Antonio Di Loria ◽

Cecilia Dall’Aglio ◽

Diego Piantedosi ◽

Elvio Lepri ◽

...

Keyword(s):

Immune System ◽

Skin Diseases ◽

Skin Inflammation ◽

Normal Weight ◽

Hair Follicles ◽

Obese Group ◽

System Control ◽

System Composition ◽

Skin Biology

Obesity predisposes to several health problems including skin diseases. However, information on the relationship between obesity and skin disorders in pets is very scarce. Leptin (LEP) is mainly produced by adipose tissue and has a prominent role in skin biology. This study evaluated the LEP system in the skin of obese dogs compared to normal-weight animals. The investigation was carried out on 10 obese (Obese group) and 10 normal-weight (Normal-weight group) dogs through Real-time PCR and immunohistochemistry. Cells of skin associated immune system were also evaluated. No differences were evidenced between the two groups as well as skin inflammation. LEP differences were no significant, while LEPR transcript appeared 10-fold higher in obesedogs than in normal-weight ones. Immunostaining for both molecules was observed in several skin structures such as the epidermis, hair follicles, and glands. No differences appeared in the skin associated immune system composition. This study is a preliminary report showing that LEP system changes in obese dog skin. The increased LEPR expression observed in the obese group suggests that the receptor plays a modulating role in the system control. However, the exact role of LEPin the skin under obesity conditions needs further elucidation.

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