Lactate Activates Trained Immunity By Fueling The Tricarboxylic Acid Cycle And Regulating Histone Lactylation Huanhuan Cai1 by Huanhuan Cai1, 2, 11, Xueyuan Chen3, 11, Yan Liu3, 11, Yingbo Chen4, 5, 101038/S41467025585632 instant download after payment.

Yanfang Zhu1,2, Ke-Qiong Deng1,2, Hong Ren9, Huan Yan 4,5, Zeng Cai 4,5,1234567890():,;1234567890():,;Check for updatesKe Xu4,5, Li Zhou 4,5, Zhibing Lu 1,2 , Fubing Wang 10 & Shi Liu 1,2,4,5Trained immunity refers to the long-term memory of the innate immune cells.However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sourcesimpact glucose contribution to the tricarboxylic acid (TCA) cycle and enhancecytokine production of trained monocytes. Our experiments demonstrate thattrained monocytes preferentially employe lactate over glucose as a TCA cyclesubstrate, and lactate metabolism is required for trained immune cellresponses to bacterial and fungal infection. Except for the contribution to theTCA cycle, endogenous lactate or exogenous lactate also supports trainedimmunity by regulating histone lactylation. Further transcriptome analysis,ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatinaccessibility in a manner dependent histone lactylation. Inhibiting lactatedependent metabolism by silencing lactate dehydrogenase A (LDHA) impairsboth lactate fueled the TCA cycle and histone lactylation. These findingssuggest that lactate is the hub of immunometabolic and epigenetic programsin trained immunity.