ABSTRACT
Serine metabolism is involved in the fate decisions of immune cells; however, whether and how de novo serine synthesis shapes innate immune cell function remain unknown. Here, we first demonstrated that inflammatory macrophages have high expression of phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme of de novo serine synthesis) via nuclear factor κB signaling. Notably, the pharmacological inhibition or genetic modulation of PHGDH limits macrophage interleukin (IL)-1ß production through NAD+ accumulation and subsequent NAD+-dependent SIRT1 and SIRT3 expression and activity. Mechanistically, PHGDH not only sustains IL-1ß expression through H3K9/27 acetylation-mediated transcriptional activation of Toll-like receptor 4 but also supports IL-1ß maturation via NLRP3-K21/22/24/ASC-K21/22/24 acetylation-mediated activation of the NLRP3 inflammasome. Moreover, mice with myeloid-specific depletion of Phgdh show alleviated inflammatory responses in lipopolysaccharide-induced systemic inflammation. This study reveals a network by which a metabolic enzyme, involved in de novo serine synthesis, mediates post-translational modifications and epigenetic regulation to orchestrate IL-1ß production, providing a potential inflammatory disease target.
Subject(s)
NAD , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , Mice , Acetylation , Epigenesis, Genetic , Inflammasomes/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Macrophages/metabolism , NAD/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Protein Processing, Post-Translational , Serine/metabolismABSTRACT
Animal antimicrobial peptides (AMPs), known as broad-spectrum and high-efficiency antibacterial activity, are important effector molecules in innate immune system. AMPs not only have antimicrobial, antiviral and antitumor effects but also exhibit important effects in vivo, such as anti-inflammatory response, recruiting immune cells, promoting epithelial damage repair, and promoting phagocytosis of bacteria. However, research on the application of AMPs is incomplete and controversial. This review mainly introduces the classification of AMPs, biological functions, as well as the mechanisms of action, expression rules, and nutrition regulation from three perspectives, aiming to provide important information for the application of AMPs.
