Exogenous L-Serine Alleviates Pasteurella multocida-Induced Inflammation by Reprogramming the Transcription and Metabolism of Macrophages

P. multocida is notorious for inducing excessive inflammation with high lethality in multiple animals, such as cattle, pigs, and chickens. Our previous study revealed that L-serine was decreased in the lungs of mice infected with P. multocida capsular type A strain CQ2 (PmCQ2), and 2 mg/kg of L-serine could alleviate PmCQ2-induced lung inflammation in vivo, which may largely depend on macrophages. However, the underlying intrinsic alterations remain unknown. Here, we demonstrated that 10 mM of L-serine significantly inhibited the release of inflammatory cytokines (e.g., IL-1β and TNF-α) by blocking inflammasome activation (including NALP1, NLRP3, NLRC4, AIM2, and Caspase-1) in PmCQ2-infected macrophages. Furthermore, the results of RNA-seq and metabonomics revealed that exogenous L-serine supplementation substantially reprogrammed macrophage transcription and metabolism. Mechanically, L-serine reduced inflammatory responses via the inhibition of glycolysis in macrophages based on a seahorse assay. Together, these findings characterize the intrinsic molecular alterations in activated macrophages and provide new targets for modulating P. multocida infection-induced macrophage inflammation.