Lysosomotropic beta blockers induce oxidative stress and IL23A production in Langerhans cells
| العنوان: | Lysosomotropic beta blockers induce oxidative stress and IL23A production in Langerhans cells |
|---|---|
| المؤلفون: | Gerrit Müller, Charlotte Lübow, Günther Weindl |
| المصدر: | Autophagy |
| بيانات النشر: | Informa UK Limited, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Inflammasomes, Interleukin 1 family, Adrenergic beta-Antagonists, Inflammation, Endosomes, Pharmacology, Biology, medicine.disease_cause, Interleukin-23, Mitogen-Activated Protein Kinase 14, 03 medical and health sciences, Lysosomal-Associated Membrane Protein 1, NLR Family, Pyrin Domain-Containing 3 Protein, Receptors, Adrenergic, beta, Autophagy, medicine, Humans, Beta (finance), Molecular Biology, chemistry.chemical_classification, Reactive oxygen species, 030102 biochemistry & molecular biology, NF-kappa B, Cell Differentiation, Chloroquine, Dendritic Cells, Cell Biology, Interleukin-12, Propranolol, Ubiquitinated Proteins, Mitochondria, Oxidative Stress, 030104 developmental biology, Gene Expression Regulation, chemistry, Langerhans Cells, Th17 Cells, Inflammation Mediators, medicine.symptom, Lysosomes, Reactive Oxygen Species, Oxidative stress, Th17 cytokines, Signal Transduction, Research Paper |
| الوصف: | Oxidative stress and T(h)17 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. |
| تدمد: | 1554-8635 1554-8627 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6bc52b2ddb90402d9bd0908c5dfab493 https://doi.org/10.1080/15548627.2019.1686728 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....6bc52b2ddb90402d9bd0908c5dfab493 |
| قاعدة البيانات: | OpenAIRE |
PDF full text from Publisher | تدمد: | 15548635 15548627 |
|---|