Non-receptor tyrosine kinase c-Abl downstream of C-type lectin receptors regulates innate antifungal immunity through c-Cbl/MAPK pathway

TL;DR

This study shows that the c-Abl kinase helps protect against fungal infections by regulating immune responses through the c-Cbl/MAPK pathway.

Contribution

The study identifies a novel c-Abl/c-Cbl/MAPK signaling axis in dendritic cells that regulates antifungal immunity.

Findings

Inhibiting c-Abl reduces survival and increases fungal burden in mice infected with Candida albicans.

c-Abl inhibition decreases production of key cytokines in dendritic cells after fungal stimulation.

The c-Abl/c-Cbl/MAPK pathway is critical for p38 and ERK1/2 activation in antifungal immunity.

Abstract

Non-receptor tyrosine kinase c-Abl is critical for host defense against bacterial and viral infections, yet its role in antifungal immunity remains elusive. Here, we report that inhibition of c-Abl with flumatinib mesylate significantly impairs the survival rate and exacerbates fungal burden in mice infected with Candida albicans. Our findings reveal that c-Abl inhibition reduces production of TNF-α, IL-10, and IL-12 in bone marrow-derived dendritic cells (BMDCs) after stimulation with fungal β-glucan or α-mannan. Mechanistically, c-Abl inhibition significantly blocks p38 and extracellular signal-regulated kinases 1/2 (ERK1/2) activation in BMDCs after α-mannan stimulation in a c-Cbl dependent manner. Collectively, our study uncovers a c-Abl/c-Cbl/MAPK signaling axis in dendritic cells that governs antifungal innate immunity, highlighting c-Cbl as a critical downstream mediator linking c-Abl to host defense against C. albicans. Our findings provide a mechanistic basis for fungal risk assessment in cancer patients treated with c-Abl inhibitors.

Figures