Lysosomotropic beta blockers induce oxidative stress and IL23A production in Langerhans cells

Autophagy. 2020 Aug;16(8):1380-1395. doi: 10.1080/15548627.2019.1686728. Epub 2019 Nov 7.

Abstract

Oxidative stress and Th17 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.

Keywords: Beta blockers; IL1; IL23A; MAPK14/p38; dendritic cells; inflammation; reactive oxygen species; skin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology*
  • Autophagy / drug effects
  • Cell Differentiation / drug effects
  • Chloroquine / pharmacology
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Endosomes / drug effects
  • Endosomes / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammasomes / metabolism
  • Inflammation Mediators / metabolism
  • Interleukin-12 / genetics
  • Interleukin-12 / metabolism
  • Interleukin-23 / biosynthesis*
  • Langerhans Cells / drug effects
  • Langerhans Cells / metabolism*
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Lysosomes / drug effects
  • Lysosomes / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • NF-kappa B / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Oxidative Stress / drug effects*
  • Propranolol / pharmacology
  • Reactive Oxygen Species / metabolism
  • Receptors, Adrenergic, beta / metabolism
  • Signal Transduction
  • Th17 Cells / cytology
  • Th17 Cells / drug effects
  • Ubiquitinated Proteins / metabolism

Substances

  • Adrenergic beta-Antagonists
  • Inflammasomes
  • Inflammation Mediators
  • Interleukin-23
  • Lysosomal-Associated Membrane Protein 1
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species
  • Receptors, Adrenergic, beta
  • Ubiquitinated Proteins
  • Interleukin-12
  • Chloroquine
  • Propranolol
  • Mitogen-Activated Protein Kinase 14

Grants and funding

This work was supported by the German Ministry of Education and Research under Grant [031A262A].