A simple tool for evaluation of inflammation in psoriasis: Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio as markers in psoriasis patients and related murine models of psoriasis-like skin disease.

Objective parameters to quantify psoriatic inflammation are needed for interdisciplinary patient care, as well as preclinical experimental models. This study evaluates neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in psoriasis patients and five murine models of psoriasis-like skin disease based on topical imiquimod application and overexpression of IL-17A under different promotors. We performed a single-center prospective observational study in a German population, investigating psoriasis patients prior to, 4 weeks, and 16 weeks post begin of systemic anti-inflammatory therapy. Psoriasis area and severity index (PASI), blood count, and C-reactive protein (CRP) levels were attained at each timepoint. Additionally, five murine models of psoriasis-like skin disease involving five distinct experimental procedures differing in time of disease-onset and severity were investigated regarding PLR and NLR. Of 43 recruited psoriasis patients, 34 patients were followed up to 16 weeks. The cohort was 69.77% male, showing a median age of 32.0 years (range 19.0-67.0; IQR 26). The median PASI decreased from 16.35 (8.0-50.0; 10.20) to 1.6 (0-10.3; 2.56) after 16 weeks of systemic therapy. Spearman's correlation showed statistically significant positive correlation for NLR with PASI (rs = 0.27, p = 0.006), however not for PLR. NLR, but not PLR, was significantly associated with PASI in a multiple linear regression analysis including age, sex, psoriasis arthritis, and smoking. In the murine models of psoriasis-like skin disease, both NLR and PLR were significantly increased in the acute-severe models compared to controls (p < 0.001, p = 0.005, and p = 0.02, respectively), demonstrating gradually less increased values from severe-acute to mild-late-onset psoriatic phenotype. NLR was significantly associated with PASI in psoriatic patients as well as psoriatic phenotype in different murine psoriasis models. Our data warrants investigation of NLR in psoriasis patients and preclinical psoriasis models as an objective biomarker of psoriatic skin inflammation. KEY MESSAGES : NLR, but not PLR, showed a statistically significant positive correlation with Psoriasis Area and Severity Index (PASI) in our human psoriasis cohort. Both NLR and PLR were significantly increased in murine psoriasis models compared to matched controls, with gradually less increased values from severe-acute to mild-late-onset psoriatic phenotype. NLR may represent an easily available, cheap, and objective parameter to monitor psoriatic inflammation in both clinical patient routine, as well as preclinical experimental murine models.

Reactive oxygen species produced by myeloid cells in psoriasis as a potential biofactor contributing to the development of vascular inflammation.

Psoriasis is an immune-mediated inflammatory skin disease driven by interleukin-17A (IL-17A) and associated with cardiovascular dysfunction. We used a severe psoriasis mouse model of keratinocyte IL-17A overexpression (K14-IL-17Aind/+ , IL-17Aind/+ control mice) to investigate the activity of neutrophils and a potential cellular interconnection between skin and vasculature. Levels of dermal reactive oxygen species (ROS) and their release by neutrophils were measured by lucigenin-/luminol-based assays, respectively. Quantitative RT-PCR determined neutrophilic activity and inflammation-related markers in skin and aorta. To track skin-derived immune cells, we used PhAM-K14-IL-17Aind/+ mice allowing us to mark all cells in the skin by photoconversion of a fluorescent protein to analyze their migration into spleen, aorta, and lymph nodes by flow cytometry. Compared to controls, K14-IL-17Aind/+ mice exhibited elevated ROS levels in the skin and a higher neutrophilic oxidative burst accompanied by the upregulation of several activation markers. In line with these results psoriatic mice displayed elevated expression of genes involved in neutrophil migration (e.g., Cxcl2 and S100a9) in skin and aorta. However, no direct immune cell migration from the psoriatic skin into the aortic vessel wall was observed. Neutrophils of psoriatic mice showed an activated phenotype, but no direct cellular migration from the skin to the vasculature was observed. This suggests that highly active vasculature-invading neutrophils must originate directly from the bone marrow. Hence, the skin-vasculature crosstalk in psoriasis is most likely based on the systemic effects of the autoimmune skin disease, emphasizing the importance of a systemic therapeutic approach for psoriasis patients.

Aircraft noise exposure induces pro-inflammatory vascular conditioning and amplifies vascular dysfunction and impairment of cardiac function after myocardial infarction.

AIMS: Traffic noise may play an important role in the development and deterioration of ischaemic heart disease. Thus, we sought to determine the mechanisms of cardiovascular dysfunction and inflammation induced by aircraft noise in a mouse model of myocardial infarction (MI) and in humans with incident MI. METHODS AND RESULTS: C57BL/6J mice were exposed to noise alone (average sound pressure level 72 dB; peak level 85 dB) for up to 4 days, resulting in pro-inflammatory aortic gene expression in the myeloid cell adhesion/diapedesis pathways. The noise alone promoted adhesion and infiltration of inflammatory myeloid cells in vascular/cardiac tissue, paralleled by an increased percentage of leucocytes with a pro-inflammatory, reactive oxygen species (ROS)-producing phenotype and augmented expression of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase type 2 (Nox2)/phosphorylation of nuclear factor 'kappa light chain enhancer' of activated B-cells (phospho-NFκB) in peripheral blood. Ligation of the left anterior descending artery resulted in worsening of cardiac function, pronounced cardiac infiltration of CD11b+ myeloid cells and Ly6Chigh monocytes, and induction of interleukin (IL) 6, IL-1ß, CCL-2, and Nox2, being aggravated by noise exposure prior to MI. MI induced stronger endothelial dysfunction and more pronounced increases in vascular ROS in animals preconditioned with noise. Participants of the population-based Gutenberg Health Cohort Study (median follow-up:11.4 years) with incident MI revealed elevated C-reactive protein at baseline and worse left ventricular ejection fraction (LVEF) after MI in case of a history of noise exposure and subsequent annoyance development. CONCLUSION: Aircraft noise exposure before MI substantially amplifies subsequent cardiovascular inflammation and aggravates ischaemic heart failure, facilitated by a pro-inflammatory vascular conditioning. Our translational results suggest that measures to reduce environmental noise exposure will be helpful in improving the clinical outcome of subjects with MI.Key questionKey finding Take-home-MessageAircraft noise exposure before MI substantially amplifies cardiovascular inflammation and aggravates cardiac impairment after MI.

Effects of Dietary Protein Intake on Cutaneous and Systemic Inflammation in Mice with Acute Experimental Psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory disorder, primarily characterized by skin plaques. It is linked to co-morbidities including cardiovascular disease and metabolic syndrome. Several studies demonstrate that dietary habits can influence psoriasis development and severity. However, the effect of different dietary protein levels on psoriasis development and severity is poorly understood. In this study, we examine the influence of dietary protein on psoriasis-like skin disease in mice. METHODS: We fed male C57BL/6J mice with regular, low protein and high protein chow for 4 weeks. Afterwards, we induced psoriasis-like skin disease by topical imiquimod (IMQ)-treatment on ear and back skin. The local cutaneous and systemic inflammatory response was investigated using flow cytometry analysis, histology and quantitative rt-PCR. RESULTS: After 5 days of IMQ-treatment, both diets reduced bodyweight in mice, whereas only the high protein diet slightly aggravated IMQ-induced skin inflammation. IMQ-treatment induced infiltration of myeloid cells, neutrophils, and monocytes/macrophages into skin and spleen independently of diet. After IMQ-treatment, circulating neutrophils and reactive oxygen species were increased in mice on low and high protein diets. CONCLUSION: Different dietary protein levels had no striking effect on IMQ-induced psoriasis but aggravated the systemic pro-inflammatory phenotype.