Epithelial-Immune Metabolic Codependency Fuels Inflammatory Disease [Bulk RNA-seq]
Inflammatory skin diseases are spurred by unchecked immune-epithelial circuits. Although the function of cytokine and chemokine signals in facilitating this crosstalk is well established, the specific metabolic mediators involved and their simultaneous contribution to dysregulation of these two distinct cellular compartments is unclear. Here, we employed scRNA-seq, spatial transcriptomics, and immunofluorescence across multiple disease indications to elucidate a dysfunctional epithelial state marked by Hypoxia Inducible Factor 1 alpha (HIF1?). Ex vivo HIF1? blockade of human Psoriasis (PsO) lesions led to a reduction in pathological gene expression via modulation of glucose metabolism. Epidermal-specific loss of HIF1? or its transcriptional target, glucose transporter 1, curtailed both epidermal pathology and the cutaneous immune response in murine PsO. Glycolytic metabolism sustained epithelial hyperproliferation and differentiation, while lactate, its terminal product, was crucial for sustaining Type 17 response. Notably, inhibition of lactate dehydrogenase A or the lactate transporters MCT1/4 selectively attenuated the Type 17 response, underscoring a divergent requirement for glucose and lactate in epithelial and immune cells, respectively. Collectively, these findings identify therapeutically targetable immune-epithelial circuits by unveiling a remarkable coordination of metabolic processed between the epithelial and immune compartments in inflammatory skin disease. Overall design: Bulk RNA sequencing from two experimental studies assessing effect of dampening HIF1? in inflammatory disease: (1) Human samples: 4 mm full-thickness punch biopsies from human lesional psoriatic skin and healthy skin were subjected to DMSO vehicle, 10µM of BAY87-2243, and 500nM of calcipotriol and 5µM of betamethasone dipropionate (standard of care) for 24 hours and submitted for sequencing to assess transcriptional differences between treatment conditions. (2) Murine samples: backskin taken after three days of imiquimod-treated WT or epithelial-specific HIF1? knockout mice for comparative gene expression analyses.