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Plaque psoriasis is an autoinflammatory and autoimmune skin disease, affecting 1-3% of the population worldwide. Previously, high levels of IL-36 family cytokines were found in psoriatic skin lesions, thereby contributing to keratinocyte hyperproliferation and infiltration of immune cells such as neutrophils. While treatment with anti-IL36 receptor (IL36R) antibodies was recently approved for generalized pustular psoriasis (GPP), it remains unclear, if targeting the IL36R might also inhibit plaque psoriasis. Here we show that antibody-mediated inhibition of IL36R is sufficient to suppress imiquimod-induced psoriasis-like skin inflammation and represses the disease’s development in a model that depends on IL-17A overexpression in the skin. Importantly, treatment with anti-IL36R antibodies inhibited skin inflammation and attenuated psoriasis-associated, systemic inflammation. This is possibly due to a widespread effect of IL36R inhibition, which not only suppresses pro-inflammatory gene expression in keratinocytes, but also the activation of other immune cells such as T-cells or dendritic cells. In conclusion, we propose that inhibition of the IL-36 signaling pathway might constitute an attractive, alternative approach for treating IL-17A-driven psoriasis and psoriasis-linked comorbidities.

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 messagesNLR, 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.

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.

Necrosis is a form of cell death that is detrimental to the affected tissue because the cell ruptures and releases its content (reactive oxygen species among others) into the extracellular space. Clusterin (CLU), a cytoprotective extracellular chaperone has been shown to be upregulated in the face of necrosis. We here show that in addition to CLU upregulation, necrotic cell lysates induce JNK/SAPK signaling, the IRE1α branch of the unfolded protein response (UPR), the MAPK/ERK1/2, and the mTOR signaling pathways and results in an enhanced proliferation of the vital surrounding cells. We name this novel response mechanism: Necrosisinduced Proliferation (NiP).