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

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.