Spleen tyrosine kinase inhibition ameliorates airway inflammation through modulation of NLRP3 inflammosome and Th17/Treg axis

Abstract

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⁺FOXP3⁺ T cells that accompanied reduced T cell proliferation. Decreased IgA in the Bronchoalveolar lavage (BAL) fluid and serum also indicated the immunosuppressive potential of SYK inhibition. Histopathology data revealed that repeated β-glucan challenge caused substantial pulmonary damage, as indicated by septal thickening and interstitial lymphocytic, neutrophil and granulocyte recruitment. These processes were effectively prevented by SYK inhibition, resulting in lung protection. Collectively, our findings suggest that SYK inhibition ameliorates dectin-1- mediated detrimental pulmonary inflammation and subsequent tissue damage. Therefore, SYK can be a new target gene in the therapeutic approach against fungal induced airway inflammation.

Keywords: 3,4-Methylenedioxy-β-nitrostyrene; A. fumigatus; Inflammasome; Spleen tyrosine kinase; Th17/Treg; β-Glucan.