Oxidative stress and T_h17 cytokines are important mediators of inflammation. Treatment with beta-adrenoceptor (ADRB) antagonists (beta-blockers) is associated with induction or aggravation of psoriasis-like skin inflammation, yet the underlying mechanisms are poorly understood. Herein, we identify lysosomotropic beta-blockers as critical inducers of IL23A in human monocyte-derived Langerhans-like cells under sterile-inflammatory conditions. Cytokine release was not mediated by cAMP, suggesting the involvement of ADRB-independent pathways. NFKB/NF-κB and MAPK14/p38 activation was required for propranolol-induced IL23A secretion whereas the NLRP3 inflammasome was dispensable. MAPK14 regulated recruitment of RELB to IL23A promoter regions. Without affecting the ubiquitin-proteasome pathway, propranolol increased lysosomal pH and induced a late-stage block in macroautophagy/autophagy. Propranolol specifically induced reactive oxygen species production, which was critical for IL23A secretion, in Langerhans-like cells. Our findings provide insight into a potentially crucial immunoregulatory mechanism in cutaneous dendritic cells that may explain how lysosomotropic drugs regulate inflammatory responses.

Abbreviations

ATF: activating transcription factor; DC: dendritic cell; ChIP: chromatin immunoprecipitation; gDNA: genomic DNA; IL: interleukin; LAMP1: lysosomal associated membrane protein 1; LC: Langerhans cell; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MoDC: monocyte-derived DC; MoLC: monocyte-derived Langerhans-like cell; mtDNA: mitochondrial DNA; NAC: N-acetyl-L-cysteine; NLRP3: NLR family pyrin domain containing 3; PBMC: peripheral blood mononuclear cell; PI: propidium iodide; PYCARD/ASC: PYD and CARD domain containing; qRT-PCR: quantitative real-time PCR; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TLR: Toll-like receptor; TRAF6: TNF receptor associated factor 6; TNF: tumor necrosis factor; Ub: ubiquitin.

中文翻译：

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溶致同质性β受体阻滞剂在朗格罕斯细胞中诱导氧化应激和IL23A产生。

氧化应激和T _h 17细胞因子是炎症的重要介质。用β-肾上腺素能受体（ADRB）拮抗剂（β-受体阻滞剂）治疗与牛皮癣样皮肤炎症的诱发或加重有关，但其潜在机制尚不清楚。在本文中，我们确定溶血同质性β-受体阻滞剂是在无菌炎症条件下人单核细胞衍生的朗格汉斯样细胞中IL23A的关键诱导物。细胞因子的释放不是由cAMP介导的，这提示了与ADRB无关的途径的参与。普萘洛尔诱导的IL23A分泌需要NFKB /NF-κB和MAPK14 / p38激活，而NLRP3炎性小体是可有可无的。MAPK14调节RELB向IL23A的募集启动子区域。在不影响泛素-蛋白酶体途径的情况下，普萘洛尔提高了溶酶体的pH值并诱导了巨噬细胞自噬/自噬的晚期阻滞。普萘洛尔在朗格汉斯样细胞中特异性诱导活性氧的产生，这对于IL23A分泌至关重要。我们的发现为皮肤树突状细胞中潜在的至关重要的免疫调节机制提供了见解，这可能解释了溶溶同性药物如何调节炎症反应。

缩略语

ATF：激活转录因子；DC：树突状细胞；ChIP：染色质免疫沉淀；gDNA：基因组DNA；IL：白介素；LAMP1：溶酶体相关膜蛋白1；LC：朗格汉斯细胞；LPS：脂多糖；MAP1LC3 / LC3：微管相关蛋白1轻链3；MAPK：有丝分裂原激活的蛋白激酶；MoDC：单核细胞来源的DC；MoLC：单核细胞衍生的朗格汉斯样细胞；mtDNA：线粒体DNA；NAC：N-乙酰基-L-半胱氨酸；NLRP3：含有3个的NLR家族的吡啶结构域；PBMC：外周血单个核细胞；PI：碘化丙啶；PYCARD / ASC：包含PYD和CARD域；qRT-PCR：实时定量PCR；ROS：活性氧；SQSTM1 / p62：螯合体1；TLR：Toll样受体；TRAF6：TNF受体相关因子6；TNF：肿瘤坏死因子；UB：泛素。