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

ABSTRACT: 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. 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

ORGANISM(S): Homo Sapiens

SUBMITTER: Ming Xia

PROVIDER: PXD072439 | iProX | Fri Dec 26 00:00:00 GMT 2025

REPOSITORIES: iProX

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

Project description: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.

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Project description:Chronic rhinosinusitis with nasal polyps is a hallmaerk disease in the field of upper airway immunity and chronic inflammation. Diverse inflammatory patterns between nasal polyps have been described in patients that hail from disparate racial and geographic backgrounds. However, it remains unclear whether these immunologic differences in nasal polyps between racial groups are driven by unique molecular mechanisms. We interrogated the gene expression profiles of nasal polyp tissues from Western (United States) and East Asian (Japan) descent, compared to ethmoid sinus tissue controls.

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Proteomic analysis of mucus from chronic rhinosinusitis patients with or without nasal polyps

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