Figure 1. Integration of lipid homeostasis into the macrophage host defense response.

Selected roles for cholesterol, oxysterols, and oxPLs in the macrophage innate immune response are depicted. IFN-β induced by virus or LPS feeds back through autocrine/paracrine signaling, upregulating Ch25h and also inhibiting the cholesterol (CHOL) synthesis pathway. 25HC, the product of Ch25h, exerts several effects, inhibiting viral fusion and proliferation, inhibiting inflammasome-dependent IL-1β production, but also augmenting induction of select proinflammatory genes, such as IL-6. IFN-β-dependent inhibition of cholesterol biosynthesis augments antiviral defense by enhancing stimulator of Ifn genes–dependent IFN-β induction and also possibly by depleting lipid rafts, through which several viruses bud from host cells. OxPL induced in the inflamed lung and not cleared by scavenger receptors such as macrophage receptor with collagenous structure may induce TLR4-dependent proinflammatory cytokines via the adaptor protein TIR-domain–containing adaptor-inducing IFN-β (Trif), aggravating lung injury. Ifnar, Ifnα/β receptor.