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

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.

scholarly journals Exacerbated Imiquimod-Induced Psoriasis-Like Skin Inflammation in IRF5-Deficient Mice

2020 ◽  
Vol 21 (10) ◽  
pp. 3681
Author(s):  
Momoko Nakao ◽  
Tomomitsu Miyagaki ◽  
Makoto Sugaya ◽  
Shinichi Sato
Keyword(s):  
Critical Role ◽  
Skin Inflammation ◽  
Interferon Α ◽  
Toll Like Receptor ◽  
Adaptive Immune ◽  
Th17 Cytokines ◽  
Factor Α ◽  
Deficient Mice ◽  
Necrosis Factor

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis.

scholarly journals Fas/FasL Pathway Participates in Regulation of Antiviral and Inflammatory Response during Mousepox Infection of Lungs

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Karolina Bień ◽  
Justyna Sokołowska ◽  
Piotr Bąska ◽  
Zuzanna Nowak ◽  
Wanda Stankiewicz ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Response ◽  
Fas Ligand ◽  
Antiviral Response ◽  
Target Cells ◽  
Local Inflammatory Response ◽  
Induced Apoptosis ◽  
Deficient Mice

Fas receptor-Fas ligand (FasL) signalling is involved in apoptosis of immune cells as well as of the virus infected target cells but increasing evidence accumulates on Fas as a mediator of apoptosis-independent processes such as induction of activating and proinflammatory signals. In this study, we examined the role of Fas/FasL pathway in inflammatory and antiviral response in lungs using a mousepox model applied to C57BL6/J, B6. MRL-Faslpr/J, and B6Smn.C3-Faslgld/J mice. Ectromelia virus (ECTV) infection of Fas- and FasL-deficient mice led to increased virus titers in lungs and decreased migration of IFN-γexpressing NK cells, CD4+ T cells, CD8+ T cells, and decreased IL-15 expression. The lungs of ECTV-infected Fas- and FasL-deficient mice showed significant inflammation during later phases of infection accompanied by decreased expression of anti-inflammatory IL-10 and TGF-β1 cytokines and disturbances in CXCL1 and CXCL9 expression. Experiments in vitro demonstrated that ECTV-infected cultures of epithelial cells, but not macrophages, upregulate Fas and FasL and are susceptible to Fas-induced apoptosis. Our study demonstrates that Fas/FasL pathway during ECTV infection of the lungs plays an important role in controlling local inflammatory response and mounting of antiviral response.

scholarly journals Involvement of Dendritic Cells and Th17 Cells in Induced Tertiary Lymphoid Structures in a Chronic Beryllium Disease Mouse Model

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Alex KleinJan ◽  
Menno van Nimwegen ◽  
Karolina Leman ◽  
Ke-xin Wen ◽  
Louis Boon ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mouse Model ◽  
Inflammatory Disorder ◽  
Chronic Beryllium Disease ◽  
Th17 Lymphocytes ◽  
Beryllium Disease ◽  
Deficient Mice

Rationale. Sarcoidosis is a systemic inflammatory disorder characterized by the presence of granulomas in various organs, most commonly in the lungs. Although the ethology is unknown, sarcoidosis is thought to be mediated by T helper (Th)1 and Th17 lymphocytes. Chronic airway exposure to beryllium metal leads to chronic beryllium disease (CBD), which shares similarities with pulmonary sarcoidosis. Objective. To study airway pathophysiology and the role of dendritic cells (DCs) and IL-17 receptor (IL-17R) signals in a mouse model for CBD. Methods. Here, we present a CBD mouse model in which mice were exposed to beryllium during three weeks. We also exposed IL-17R-deficient mice and mice in which DCs were depleted. Results. Eight weeks after the initial beryllium exposure, an inflammatory response was detected in the lungs. Mice displayed inflammation of the lower airways that included focal dense infiltrates, granuloma-like foci, and tertiary lymphoid structure (TLS) containing T cells, B cells, and germinal centers. Alveolar cell analysis showed significantly increased numbers of CD4+ T cells expressing IFNγ, IL-17, or both cytokines. The pathogenic role of IL-17R signals was demonstrated in IL-17R-deficient mice, which had strongly reduced lung inflammation and TLS development following beryllium exposure. In CBD mice, pulmonary DC subsets including CD103+ conventional DCs (cDCs), CD11b+ cDCs, and monocyte-derived DCs (moDCs) were also prominently increased. We used diphtheria toxin receptor-mediated targeted cell ablation to conditionally deplete DCs and found that DCs are essential for the maintenance of TLS in CBD. Furthermore, the presence of antinuclear autoantibodies in the serum of CBD mice showed that CBD had characteristics of autoimmune disease. Conclusions. We generated a translational model of sarcoidosis driven by beryllium and show that DCs and IL-17R signals play a pathophysiological role in CBD development as well as in established CBD in vivo.

scholarly journals Collagen-induced Arthritis Is Reduced in 5-Lipoxygenase-activating Protein-deficient Mice

1997 ◽  
Vol 185 (6) ◽  
pp. 1123-1130 ◽  
Author(s):  
Richard J. Griffiths ◽  
MaryAlice Smith ◽  
Marsha L. Roach ◽  
Jeffrey L. Stock ◽  
Ethan J. Stam ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Es Cells ◽  
Embryonic Stem ◽  
Human Rheumatoid Arthritis ◽  
Wild Type ◽  
Collagen Induced Arthritis ◽  
Chronic Inflammatory Response ◽  
Antibody Levels ◽  
Deficient Mice

Collagen-induced arthritis in the DBA/1 mouse is an experimental model of human rheumatoid arthritis. To examine the role of leukotrienes in the pathogenesis of this disease, we have developed embryonic stem (ES) cells from this mouse strain. Here, we report that DBA/1 mice made deficient in 5-lipoxygenase-activating protein (FLAP) by gene targeting in ES cells develop and grow normally. Zymosan-stimulated leukotriene production in the peritoneal cavity of these mice is undetectable, whereas they produce substantial amounts of prostaglandins. The inflammatory response to zymosan is reduced in FLAP-deficient mice. The severity of collagen-induced arthritis in the FLAP-deficient mice was substantially reduced when compared with wild-type or heterozygous animals. This was not due to an immunosuppressive effect, because anti-collagen antibody levels were similar in wild-type and FLAP-deficient mice. These data demonstrate that leukotrienes play an essential role in both the acute and chronic inflammatory response in mice.

scholarly journals Dj1 deficiency protects against atherosclerosis with anti-inflammatory response in macrophages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tharini Sivasubramaniyam ◽  
Jiaqi Yang ◽  
Henry S. Cheng ◽  
Alexandra Zyla ◽  
Angela Li ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherogenic Diet ◽  
Whole Body ◽  
Anti Oxidant ◽  
Anti Inflammatory ◽  
Atherosclerosis Treatment ◽  
Deficient Mice

AbstractInflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive. To assess the role of Dj1 in atherogenesis, we generated whole-body Dj1-deficient atherosclerosis-prone Apoe null mice (Dj1−/−Apoe−/−). After 21 weeks of atherogenic diet, Dj1−/− Apoe−/−mice were protected against atherosclerosis with significantly reduced plaque macrophage content. To assess whether haematopoietic or parenchymal Dj1 contributed to atheroprotection in Dj1-deficient mice, we performed bone-marrow (BM) transplantation and show that Dj1-deficient BM contributed to their attenuation in atherosclerosis. To assess cell-autonomous role of macrophage Dj1 in atheroprotection, BM-derived macrophages from Dj1-deficient mice and Dj1-silenced macrophages were assessed in response to oxidized low-density lipoprotein (oxLDL). In both cases, there was an enhanced anti-inflammatory response which may have contributed to atheroprotection in Dj1-deficient mice. There was also an increased trend of plasma DJ-1 levels from individuals with ischemic heart disease compared to those without. Our findings indicate an atheropromoting role of Dj1 and suggests that targeting Dj1 may provide a novel therapeutic avenue for atherosclerosis treatment or prevention.

scholarly journals Loss of epidermal Evi/Wls results in a phenotype resembling psoriasiform dermatitis

2013 ◽  
Vol 210 (9) ◽  
pp. 1761-1777 ◽  
Author(s):  
Iris Augustin ◽  
Julia Gross ◽  
Daniel Baumann ◽  
Claudia Korn ◽  
Grainne Kerr ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cell ◽  
Immune Cell ◽  
Normal Skin ◽  
Conditional Knockout ◽  
Psoriatic Skin ◽  
Skin Barrier Function ◽  
Wnt Proteins ◽  
Deficient Mice

Cells of the epidermis renew constantly from germinal layer stem cells. Although epithelial cell differentiation has been studied in great detail and the role of Wnt signaling in this process is well described, the contribution of epidermal Wnt secretion in epithelial cell homeostasis remains poorly understood. To analyze the role of Wnt proteins in this process, we created a conditional knockout allele of the Wnt cargo receptor Evi/Gpr177/Wntless and studied mice that lacked Evi expression in the epidermis. We found that K14-Cre, Evi-LOF mice lost their hair during the first hair cycle, showing a reddish skin with impaired skin barrier function. Expression profiling of mutant and wild-type skin revealed up-regulation of inflammation-associated genes. Furthermore, we found that Evi expression in psoriatic skin biopsies is down-regulated, suggesting that Evi-deficient mice developed skin lesions that resemble human psoriasis. Immune cell infiltration was detected in Evi-LOF skin. Interestingly, an age-dependent depletion of dendritic epidermal T cells (DETCs) and an infiltration of γδlow T cells in Evi mutant epidermis was observed. Collectively, the described inflammatory skin phenotype in Evi-deficient mice revealed an essential role of Wnt secretion in maintaining normal skin homeostasis by enabling a balanced epidermal-dermal cross talk, which affects immune cell recruitment and DETC survival.

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