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Chronic dermatitis is a disease with large unmet need for pharmacological improvement. Dermatitis conditions are maintained and exacerbated by various cytokine actions in the context of inflammation. Interleukin 6 signal transducer (Il6st), also known as glycoprotein 130 (Gp130), is a key component for surface reception of a multitude of cytokines and transduction and amplification of their pro-inflammatory signals. We hypothesized accordingly that pharmacological inhibition of Il6st can alter dermatitis pathology. Treatment with SC-144 and bazedoxifene, two representative small molecule Il6st inhibitors with different binding modes led to moderate but significant improvement of skin conditions in a 1-chloro-2,4-dinitrobenzene animal model. Part of cytokine expressions indicating the dermatological index were normalized particularly when treated with SC-144. Pruritic behaviors were blunted, also possibly giving limited contribution to disease improvement. In psoriatic skin and itch of an imiquimod animal model, those two treatments appeared to be relatively moderate. Collectively, pharmacological inhibition of Il6st seems to lessen pathological irritation. Inversely, this experimental attempt newly implies that Il6st participates in pathological mechanisms. In conclusion, we suggest Il6st as a novel target for improving dermatitis, and that agents with suitable efficacy and safety for its modulation are translatable.

Chronic dermatitis is a disease with large unmet need for pharmacological improvement. Dermatitis conditions are maintained and exacerbated by various cytokine actions in the context of inflammation. Interleukin 6 signal transducer (Il6st), also known as glycoprotein 130 (Gp130), is a key component for surface reception of a multitude of cytokines and transduction and amplification of their pro-inflammatory signals. We hypothesized accordingly that pharmacological inhibition of Il6st can alter dermatitis pathology. Treatment with SC-144 and bazedoxifene, two representative small molecule Il6st inhibitors with different binding modes led to moderate but significant improvement of skin conditions in a 1-chloro-2,4-dinitrobenzene animal model. Part of cytokine expressions indicating the dermatological index were normalized particularly when treated with SC-144. Pruritic behaviors were blunted, also possibly giving limited contribution to disease improvement. In psoriatic skin and itch of an imiquimod animal model, those two treatments appeared to be relatively moderate. Collectively, pharmacological inhibition of Il6st seems to lessen pathological irritation. Inversely, this experimental attempt newly implies that Il6st participates in pathological mechanisms. In conclusion, we suggest Il6st as a novel target for improving dermatitis, and that agents with suitable efficacy and safety for its modulation are translatable. [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)-macrophage activation may promote RVF in PAH. Objectives: Evaluating the contribution of the NLRP3 inflammasome in RV macrophages to PAH RVF. Methods: Rats with decompensated RV hypertrophy (monocrotaline [MCT] and Sugen-5416 hypoxia [SuHx]) were compared with compensated RV hypertrophy rats (pulmonary artery banding). Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptides, and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and in vitro strategies. MCT rats were treated with SC-144 (a GP130 antagonist) or MCC950 (an NLRP3 inhibitor). Macrophage-NLRP3 activity was evaluated in patients with PAH RVF. Measurements and Main Results: Macrophages, fibrosis, and atrial natriuretic peptides were increased in MCT and SuHx RVs but not in left ventricles or pulmonary artery banding rats. Although MCT RV macrophages were inflammatory, lung macrophages were antiinflammatory. CCR2+ macrophages (monocyte-derived) were increased in MCT and SuHx RVs and highly expressed NLRP3. The macrophage-NLRP3 pathway was upregulated in patients with PAH with decompensated RVs. Cultured MCT monocytes showed NLRP3 activation, and in coculture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. In vivo, MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV macrophages and NLRP3 content, prevented STAT3 (signal transducer and activator of transcription 3) activation, and improved RV function without regressing pulmonary vascular disease. Conclusions: NLRP3-macrophage activation occurs in the decompensated RV in preclinical PAH models and patients with PAH. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH RVF results from RV inflammation rather than solely from elevated RV afterload suggests a new therapeutic paradigm. [ABSTRACT FROM AUTHOR]