3-4-methylenedioxy-beta-nitrostyrene and Aspergillosis

Repeated exposure to the fungal pathogen Aspergillus fumigates triggers spleen tyrosine kinase (SYK) signalling through dectin-1 activation, which is associated with deleterious airway inflammation. β-Glucan-induced dectin-1 signalling activates the NLRP3 inflammasome, which in turn rapidly produces IL-1β, a master regulator of inflammation. IL-1β expression results in Th17/Treg imbalance, pulmonary inflammation, and bystander tissue injury. This study reports that 3,4 methylenedioxy-β-nitrostyrene (MNS), a potent SYK inhibitor, markedly decreased the expression of pro-inflammatory cytokines and increased the expression of anti-inflammatory cytokines in vitro. Furthermore, SYK inhibition markedly decreased β-glucan-induced IL-1β expression, suggesting that SYK is indispensable for NLRP3 inflammasome activation. Decreased IL-1β expression correlated with reduced Th17 response and enhanced immunosuppressive Treg response. Notably, SYK inhibition ameliorated inflammation caused by repeated intranasal β-glucan challenge in BALB/C mice. SYK inhibition also restored the Th17/Treg balance via decreased Th17 and increased Treg responses, as evidenced by decreased IL-17 and ror-γ levels. Additionally, inhibition of SYK increased IL-10 secreting CD4

Topics: Animals; Aspergillosis; Aspergillus fumigatus; beta-Glucans; Cells, Cultured; Dioxolanes; Immunosuppression Therapy; Inflammasomes; Lectins, C-Type; Lung; Mice; Mice, Inbred BALB C; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Spleen; Syk Kinase; T-Lymphocytes, Regulatory; Th17 Cells