Defensive lipid droplets are PUFA reservoirs and suppliers driving bacterial clearance and inflammation.

Lipid droplets (LDs) rapidly form in infected cells to participate in the defense against microbes. Here, we investigate the involvement of LD lipids in the immune response. Comparative lipidomics demonstrate that in vivo host LDs accumulate polyunsaturated fatty acids (PUFAs) in LD-triglycerides and -phospholipids. Host lipid metabolism and the LD proteome are transcriptionally controlled by rapid, transient, and intricate immune programs initiated by pathogen-associated molecular patterns and relayed by cytokines such as interferons (type I and II), interleukins (IL-1β), and tumor necrosis factor. When this environment is reproduced in cultured macrophages, newly formed LDs accumulate defensive proteins, coordinate complex PUFA synthesis, and become PUFA reservoirs and suppliers. Among LD-PUFAs, the ω-6 arachidonic acid is the most actively metabolized during the initial phases of innate immunity. Released from LDs by adipose triglyceride lipase, arachidonic acid is used by macrophages for prostaglandin and thromboxane synthesis, bacterial phagocytosis, and elimination of microbes.