Pharmacological S100A8/A9-targeting blockade attenuates toluene diisocyanate-induced mixed granulocytic asthma

BACKGROUND AND OBJECTIVE: Mixed granulocytic asthma (MGA) is clinically characterized by poor responsiveness to corticosteroid and a high predisposition of refractory asthma. While emerging evidence has implicated S100A8/A9 in the pathogenesis of asthma, its specific role in MGA remains unexplored. Therefore, this study aimed to investigate the role of S100A8/A9 signaling in Toluene diisocyanate (TDI)-induced asthma. METHODS: A murine model of TDI-induced MGA was established. Asthmatic mice were treated with S100A8/A9 specific inhibitors ABR-25757 (0.5 mg/kg) or ABR-238901 (20 mg/kg), respectively. Bronchoalveolar lavage fluid (BALF) and lungs tissues were collected for subsequent analysis. RESULTS: Increased S100A8/A9 expression was observed in the airway mucosa of asthmatic subjects. TDI exposure upregulated S100A8/A9 expression in the inflammatory cells infiltrating the periairway region and in bronchial epithelial cells, accompanied by increased airway hyperresponsiveness (AHR), mixed granulocytic inflammation, significant airway smooth muscle (ASM) thickening and extensive collagen deposition. All these pathological responses were markedly attenuated by treatment with ABR-25757 or ABR-238901. Additionally, TDI sensitization and challenge increased expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), toll-like receptor 4 (TLR4) and receptor for advanced glycation end-product (RAGE), as well as elevated BALF levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Notably, the upregulated expression of ICAM-1, VCAM-1, TLR4, RAGE and IL-6 were recovered by ABR-25757 or ABR-238901. CONCLUSION: Blockade of S100A8/A9 with specific inhibitors effectively suppressed the development of TDI-induced asthma, suggesting that S100A8/A9-targeted therapy holds potential as a clinical intervention for patients with MGA.