Lactate-Mediated Cross-Talk between KRT15 and GPR68 drives Type 2 Immunity in ECRSwNP

Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) is a refractory inflammatory disease driven by type 2 immunity, yet the mechanistic link between epithelial stress and immune activation remains elusive. Here, we identify a pathogenic expansion of KRT5?KRT15? basal epithelial cells that undergo a metabolic switch to aerobic glycolysis, resulting in lactate overproduction and microenvironment acidification. Overall design: This acidic niche activates the proton-sensing receptor GPR68 on infiltrating CD4? T cells, triggering a Gq–IP1–IKK/ERK signaling cascade that promotes Th2 differentiation and cytokine release. Genetic ablation of GPR68 in CD4? T cells or its pharmacological inhibition with a natural antagonist, 3-Bn-6-Bnid-DKP, ameliorated type 2 inflammation and pathology in vivo. Thus, we define a lactate-GPR68 axis that metabolically couples epithelial dysfunction to adaptive type 2 immunity in ECRSwNP