Dataset Information

Neutrophil extracellular traps are induced in a psoriasis model of interleukin-36 receptor antagonist-deficient mice.

ABSTRACT: Loss-of-function mutations in the interleukin (IL)-36 gene IL36RN are associated with psoriasis. The importance of neutrophil extracellular traps (NETs), web-like structures composed of neutrophil DNA, in the pathogenesis of psoriasis has been unclear. Here, we aimed to clarify the role of NET signaling in the deficiency of IL36 receptor antagonist (DITRA). We evaluated the severity of psoriasis-like lesions induced by imiquimod cream treatment in Il36rn-/- mice. The mRNA levels of psoriasis-related cytokines were measured via real-time reverse transcription polymerase chain reaction, and the effects of Cl-amidine, a peptidyl arginine deiminase 4 (PAD4) inhibitor, on psoriasis-like lesions were evaluated. PAD4 is a histone-modifying enzyme that is involved in NET formation. Psoriasis area and severity index scores, epidermal thickness, and infiltrated neutrophil counts were significantly increased in Il36rn-/- mice; NET formation was confirmed pathologically. Several cytokines and chemokines were upregulated in the skin lesions of Il36rn-/- mice and Cl-amidine treatment improved these psoriasis-like lesions. These results suggest that NET formation plays an important role in the pathology of psoriasis-like lesions in these mice and might represent a promising therapeutic target for DITRA.

SUBMITTER: Watanabe S

PROVIDER: S-EPMC7678853 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Neutrophil extracellular traps are induced in a psoriasis model of interleukin-36 receptor antagonist-deficient mice.

Watanabe Soichiro S Iwata Yohei Y Fukushima Hidehiko H Saito Kenta K Tanaka Yoshihito Y Hasegawa Yurie Y Akiyama Masashi M Sugiura Kazumitsu K

Scientific reports 20201119 1

Loss-of-function mutations in the interleukin (IL)-36 gene IL36RN are associated with psoriasis. The importance of neutrophil extracellular traps (NETs), web-like structures composed of neutrophil DNA, in the pathogenesis of psoriasis has been unclear. Here, we aimed to clarify the role of NET signaling in the deficiency of IL36 receptor antagonist (DITRA). We evaluated the severity of psoriasis-like lesions induced by imiquimod cream treatment in Il36rn<sup>-/-</sup> mice. The mRNA levels of ps ...[more]

PMID: 33214582

Similar Datasets

Project description:BackgroundGeneralized pustular psoriasis (GPP) is a systemic inflammatory disease with poor outcomes, and several studies have suggested that the mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to GPP, where the polymorphism c.115+6T>C is reported to be the most common mutation of IL36RN. This study was performed to clarify and comprehensively evaluate the relationship between IL36RN gene polymorphism and the susceptibility of GPP subtypes.MethodsTo conduct a thorough literature review, studies were obtained using databases such as Pubmed, EMBASE, Cochrane, China National Knowledge Infrastructure, and the Wanfang database. Only studies published up to December 2019 were included. The quality of the research studies was estimated using the Newcastle-Ottawa scale. The total odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were pooled and analysed using STATA 14. The publication bias was evaluated through the Egger test, performed using the aforementioned software. Five common gene models were built and analysed to assess the association between the polymorphism c.115+6T>C and subtypes of GPP.ResultsA total of 10 studies were selected, including 683 cases of GPP patients. Meta-analyses showed that there was a significant statistical correlation of IL36RN mutation between GPP with or without psoriasis vulgaris (OR = 3.82, 95%CI 2.63-5.56) and between adult GPP and paediatric GPP (OR = 0.42, 95%CI 0.23-0.77). No obvious discrepancy between European patients (OR = 4.03, 95%CI 2.23-7.26) and Asian patients was found. The gene models showed clear associations between the polymorphism c.115+6T>C and GPP through the dominant model (CC+ TC vs TT, OR 2.74, 95%CI 2.06-3.64), recessive model (CC vs CT + TT, OR 4.33, 95%CI 2.84-6.60), homozygote model (CC vs TT, OR 4.37, 95%CI 2.88-6.62), heterozygote model (CT vs TT, OR 2.26, 95%CI 1.32-3.85) and allelic model (C vs T, OR 3.35, 95%CI 2.63-4.27).ConclusionThe IL36RN mutation is strongly related to GPP without psoriasis vulgaris and the early onset of GPP. Furthermore, the single-nucleotide polymorphism c.115+6T>C of the IL36RN gene plays a significant role in GPP vulnerability, especially in homozygous mutation. GPP could be a different inflammatory disease, independent of psoriasis.

Project description:In the course of atherogenesis, the spleen plays an important role in the regulation of extramedullary hematopoiesis, and in the control of circulating immune cells, which contributes to plaque progression. Here, we have investigated the role of splenic nucleotide-binding oligomerization domain 1 (NOD1) in the recruitment of circulating immune cells, as well as the involvement of this immune organ in extramedullary hematopoiesis in mice fed on a high-fat high-cholesterol diet (HFD). Under HFD conditions, the absence of NOD1 enhances the mobilization of immune cells, mainly neutrophils, from the bone marrow to the blood. To determine the effect of NOD1-dependent mobilization of immune cells under pro-atherogenic conditions, Apoe-/- and Apoe-/-Nod1-/- mice fed on HFD for 4 weeks were used. Splenic NOD1 from Apoe-/- mice was activated after feeding HFD as inferred by the phosphorylation of the NOD1 downstream targets RIPK2 and TAK1. Moreover, this activation was accompanied by the release of neutrophil extracellular traps (NETs), as determined by the increase in the expression of peptidyl arginine deiminase 4, and the identification of citrullinated histone H3 in this organ. This formation of NETs was significantly reduced in Apoe-/-Nod1-/- mice. Indeed, the presence of Ly6G+ cells and the lipidic content in the spleen of mice deficient in Apoe and Nod1 was reduced when compared to the Apoe-/- counterparts, which suggests that the mobilization and activation of circulating immune cells are altered in the absence of NOD1. Furthermore, confirming previous studies, Apoe-/-Nod1-/- mice showed a reduced atherogenic disease, and diminished recruitment of neutrophils in the spleen, compared to Apoe-/- mice. However, splenic artery ligation reduced the atherogenic burden in Apoe-/- mice an effect that, unexpectedly was lost in Apoe-/-Nod1-/- mice. Together, these results suggest that neutrophil accumulation and activity in the spleen are driven in part by NOD1 activation in mice fed on HFD, contributing in this way to regulating atherogenic progression.

Project description:Innate immune responses and rapid recruitment of leukocytes, which regulate inflammation and subsequent healing, play a key role in acute myocardial infarction (MI). Peptidylarginine deiminase 4 (PAD4) is critically involved in chromatin decondensation during the release of Neutrophil Extracellular Traps (NETs) by activated neutrophils. Alternatively, activated macrophages (M2) and accurate collagen deposition determine the repair of the infarcted heart. In this study, we investigated the impact of NETs on macrophage polarization and their role for acute cardiac inflammation and subsequent cardiac healing in a mouse model of acute MI. NETs were found to promote in vitro macrophage polarization toward a reparative phenotype. NETs suppressed pro-inflammatory macrophages (M1) under hypoxia and diminished IL-6 and TNF-? expression. Further on, NETs strongly supported M2b polarization and IL-10 expression. In cardiac fibroblasts, NETs increased TGF-ß expression under hypoxic culture conditions. PAD4-/- mice subjected to permanent ligation of the left anterior descending artery suffered from overwhelming inflammation in the acute phase of MI. Noteworthy, PAD4-/- neutrophils were unable to release NETs upon ex vivo stimulation with ionomycin or PMA, but produced significantly higher amounts of reactive oxygen species (ROS). Increased levels of circulating cell-free DNA, mitochondrial DNA and cardiac troponin were found in PAD4-/- mice in the acute phase of MI when compared to WT mice. Reduced cardiac expression of IL-6, IL-10, and M2 marker genes, as well as increased TNF-? expression, suggested a pro-inflammatory state. PAD4-/- mice displayed significantly increased cardiac MMP-2 expression under baseline conditions. At day 1, post-MI, PAD4-/- mice showed increased end-diastolic volume and increased thinning of the left ventricular wall. Interestingly, improved cardiac function, as demonstrated by significantly increased ejection fraction, was found at day 21. Altogether, our results indicate that NETs support macrophage polarization toward an M2 phenotype, thus displaying anti-inflammatory properties. PAD4 deficiency aggravates acute inflammation and increases tissue damage post-MI, partially due to the lack of NETs.

Dataset Information

Neutrophil extracellular traps are induced in a psoriasis model of interleukin-36 receptor antagonist-deficient mice.

Publications

Neutrophil extracellular traps are induced in a psoriasis model of interleukin-36 receptor antagonist-deficient mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets