TitleMetabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.
Publication TypeJournal Article
Year of Publication2024
AuthorsAyyangar U, Karkhanis A, Tay H, Afandi AFarissa Bi, Bhattacharjee O, Ks L, Lee SHan, Chan J, Raghavan S
JournalEMBO J
Date Published2024 Apr
KeywordsAnimals, Inflammation, Lactic Acid, Macrophages, Mice, Psoriasis, Skin

Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis.

Alternate JournalEMBO J
PubMed ID38418556
PubMed Central IDPMC10987662
Grant ListDBT/JRF/BET-18/1/2018/AL/60 / / Department of Biotechnology, Ministry of Science and Technology, India (DBT) /
BT/PR31418/BRB/10/1758/2019 / / Department of Biotechnology, Ministry of Science and Technology, India (DBT) /
BT/PR5981/MED/31/181/2012; 2013-2016 / / Department of Biotechnology, Ministry of Science and Technology, India (DBT) /
A18A8b0059 / / Agency for Science, Technology and Research (A*STAR) /