964 Epidermis derived lactate promotes sterile inflammation by inducing metabolic rewiring in macrophages

Chronic sterile inflammatory conditions are associated with striking changes in tissue metabolism. This is primarily due to metabolic rewiring in individual cell types that supports their effector functions. We previously reported that macrophages are the primary responders of sterile inflammatory cues in skin. During sterile inflammation, these cells acquire a pro-remodeling fate that leads to exacerbated degradation of the extracellular matrix. However, what are the critical macrophage-intrinsic and extrinsic metabolic cues that drive their functional outcomes remain to be understood. In this study, using a mouse model of sterile inflammation (beta1 integrin conditional KO embryonic skin) we elucidate a critical role of epidermis-derived lactate in driving macrophage metabolism and, in turn, its effector function – ECM degradation. We show that sterile inflammatory response in the skin results from ‘compartment separation’ of central carbon respiration chain between the epidermal and macrophage compartment. Using transcriptomic and metabolomic approaches we show that during sterile inflammation in skin, the epidermal and macrophage compartment uniquely depend on glycolysis and TCA cycle, respectively. Furthermore, we demonstrate that the glycolytic end product, lactate, released by the epidermal compartment is then utilized by the dermal macrophages to drive their TCA cycle. Through metabolic pathway inhibition studies we show that acquisition of epidermis-derived lactate by macrophages to drive TCA cycle is necessary to fulfil macrophage effector function in sterile inflammation. Taken together, our study establishes lactate as a coupler of metabolic nexus between epidermal and macrophage compartment that acts as a key driver of sterile inflammation. In addition, inhibition experiments further elucidate the therapeutic potential of targeting lactate metabolism in sterile inflammatory disease conditions.