Interplay between sterol metabolism and inflammation in myeloid cell activation and resolution. (A) Upon exposure to pathogen-associated molecular patterns or DAMPs, TLR signaling activates the MyD88–NF-κB pathway, leading to the transcription of pro-inflammatory cytokines. NF-κB also binds to the Srebf2 promoter, inducing transcription of SREBP2. After cleavage and maturation through the ER–Golgi pathway, active SREBP2 translocates to the nucleus and binds sterol regulatory elements (SREs), promoting the expression of genes involved in cholesterol biosynthesis (e.g., Hmgcr and Ldlr), which supports membrane remodelling and cell proliferation. (B) Following uptake of lipid-rich debris (e.g., myelin) via phagocytosis, lysosomal processing releases free cholesterol and fatty acids. Excess free cholesterol can be converted to oxysterols, which serve as endogenous ligands for LXRs. LXR activation promotes reverse cholesterol transport by upregulating cholesterol efflux genes (e.g., ABCA1 and ABCG1), leading to lipidation of ApoE particles. Additionally, free cholesterol may be re-esterified in the ER and stored as lipid droplets. LXR activation also transrepresses NF-κB target genes and inhibits SREBP processing, thereby contributing to both inflammation resolution and immunometabolic reprogramming. MyD88, myeloid differentiation primary response gene 88; ABCG1, ATP-binding cassette sub-family G member 1; SCAP, SREBP cleavage-activating protein; κBS, κ-B sites.