Type 2 cytokines reprogram MSCs through STAT6 to weaken their immunosuppressive potency

Inflammatory licensing endows mesenchymal stem/stromal cells (MSCs) with immunosuppressive activity, but how type 2 cytokines modify this programme remains unclear. Here we show that IL-4 and IL-13 counteract IFN-γ/TNF-α-induced MSC immunosuppression. IL-4/IL-13 co-conditioning diminished MSC-mediated protection against concanavalin A-induced acute liver injury and weakened MSC-associated suppression of T-cell proliferation and macrophage inflammatory activation. These functional changes were accompanied by reduced expression of inducible nitric oxide synthase (iNOS) and immunoregulatory chemokines, together with decreased nitrite accumulation. Genetic deletion of Stat6 substantially attenuated these effects, identifying STAT6 as a major mediator of type 2 cytokine-dependent regulation of MSC function. IL-4/IL-13 also reduced inflammatory cytokine-induced STAT1 nuclear accumulation in a STAT6-associated manner, suggesting a potential downstream regulatory mechanism. In vivo, conditional Stat6 deletion in PDGFRα-expressing stromal cells exacerbated bleomycin-induced lung injury and early fibrotic remodelling, highlighting the context-dependent functions of stromal STAT6. Together, these findings identify IL-4/IL-13–STAT6 signalling as a counter-regulatory pathway that limits MSC immunosuppressive licensing and shapes stromal responses to inflammatory microenvironments.