Epidermis Derived Lactate Promotes Sterile Inflammation by Inducing Metabolic Rewiring in Macrophages

Abstract

Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic, sterile inflammation. However, the extrinsic and intrinsic metabolic cues that direct and support macrophage functions are poorly understood. Here, we discover that during sterile inflammation in skin, the epidermal and macrophage compartment uniquely depend on glycolysis and TCA cycle, respectively. This compartment separation of the central carbon respiration chain is initiated by enhanced HIF1a expression in the epidermal compartment. Furthermore, the glycolysis derived lactate in the epidermis is utilized by the dermal macrophages to drive the TCA cycle to drive their effector functions. Notably, inhibition of lactate mediated crosstalk between the epidermal and macrophage compartment leads to inhibition of the sterile inflammatory response. Overall, the study identifies an essential role for lactate metabolite in regulating macrophage response that can be targeted to treat sterile inflammatory and skin disorders.