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Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic, sterile inflammation. However, the metabolic cues that direct and support macrophage functions are poorly understood. Here, we show that during sterile inflammation in skin, the epidermis and macrophages uniquely depend on glycolysis and TCA cycle, respectively. This compartment separation is initiated by HIF1a stabilization and enhanced glycolysis in the epidermis. The end product of glycolysis, lactate is exported and utilized by the dermal macrophages to drive their effector functions. Notably, inhibition of lactate mediated crosstalk between the epidermis and macrophages leads to inhibition of sterile inflammation. Overall, our study identifies an essential role for the metabolite lactate in regulating macrophage response that can be effectively targeted to treat skin disorders such as psoriasis.

Epidermis derived lactic acid drives sterile inflammation by augmenting pro-remodeling state in dermal macrophages.