TLR2-Arachidonic Acid Metabolism: A Novel Immunometabolic Pathway Driving Necroptosis
Description
Necroptosis, a form of programmed cell death, plays critical roles in various diseases and represents a promising therapeutic target for inflammatory conditions and tumors. However, the molecular mechanisms governing necroptosis, particularly the roles of lipid metabolism and pattern recognition receptors, remain poorly understood. Here, we show that infection with the zoonotic parasite Cryptosporidium parvum triggers necroptosis in the ileum and in Caco-2 cells. Integrated transcriptomic and metabolomic profiling revealed that C. parvum infection reprograms arachidonic acid (AA) metabolism, a pathway whose regulatory role in necroptosis has not been previously explored. Further investigation demonstrated that C. parvum induces TLR2-dependent upregulation of the key AA-metabolic enzymes FADS1 and cPLA2. This leads to AA accumulation and subsequently triggers necroptosis via the RIPK1–RIPK3–MLKL pathway. Specifically, we identified a C. parvum-derived Sec1-like protein interacts with TLR2 to drive this process. Notably, direct AA administration induced necroptosis in both Caco-2 cells and the ileum of suckling mice, where AA supplementation restricted parasite burden and ameliorated ileal pathology. Overall, these findings reveal the TLR2–AA axis as a novel immunometabolic pathway driving necroptosis, advancing our understanding of how lipid metabolism and pattern recognition receptors regulate cell death.