Inhibition of LRRK2 Ameliorates Aspergillus fumigatus Keratitis by Regulating STING Signaling Pathways

LRRK2 inhibition ameliorates A. fumigatus-induced inflammation through modulating STING signaling pathways in both HCECs and mouse models. Our results suggest that targeted inhibition of LRRK2 could be a promising strategy for FK treatment.

The protein levels of leucine-rich repeat kinase 2 (LRRK2), p-LRRK2, and stimulator of interferon genes (STING)-related proteins were assessed by western blot analysis. ELISA and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to evaluate the inflammatory response induced by Aspergillus fumigatus. Mass spectrometry was performed to identify the interaction partners of LRRK2. The glutathione S-transferase (GST) pull-down assay and co-immunoprecipitation (co-IP) were used to verify the interaction between LRRK2 and STING. Additionally, fungal load determinations and clinical score assessments were conducted to determine corneal infection in a mouse model.

The purpose of this study was to investigate the role of LRRK2 in the inflammatory response to fungal keratitis (FK) and elucidate the underlying mechanisms.

A. fumigatus stimulation promoted the phosphorylation of LRRK2 through Toll-like receptor 2 (TLR2) in human corneal epithelial cells (HCECs) and mouse corneas. LRRK2 overexpression enhanced the A. fumigatus-induced inflammatory response, and LRRK2 knockdown alleviated A. fumigatus keratitis both in vitro and in vivo. Mass spectrometry identified STING as a novel interaction partner of LRRK2. Moreover, A. fumigatus treatment enhanced the interaction between LRRK2 and STING, resulting in the phosphorylation and activation of STING. The phosphorylated STING then triggered its downstream signaling pathways, exacerbating the severity of A. fumigatus keratitis. LRRK2 inhibitor (LRRK2-IN-1) significantly mitigated the inflammatory response and corneal damage caused by A. fumigatus stimulation. Conclusions: LRRK2 inhibition ameliorates A. fumigatus-induced inflammation through modulating STING signaling pathways in both HCECs and mouse models. Our results suggest that targeted inhibition of LRRK2 could be a promising strategy for FK treatment.