TLR–TREM2-LXR signaling coordinate inflammatory activation and resolution in myeloid cells. (A) In the pro-inflammatory state, pathogen-associated molecular patterns or DAMPs activate TLR signaling via the MyD88–NF-κB axis, inducing transcription of pro-inflammatory cytokines. This state suppresses TREM2-mediated activation/phagocytosis. (B) Microglia engage TREM2–DAP12–SYK signaling upon sensing lipid-rich debris. This promotes phagocytosis, lipid processing in lysosomes, transcription of genes such as Apoe, Lpl, Axl, and Itgax, and generation of oxysterols, which activate LXR. (C) LXR activation promotes cholesterol efflux, inhibits NF-κB, and supports inflammation resolution. This pathway enables a transition to a reparative phenotype, maintaining TREM2 function and suppressing further inflammatory activation. SYK, spleen tyrosine kinase; MyD88, myeloid differentiation primary response gene 88.
Figure 3.

TLR–TREM2-LXR signaling coordinate inflammatory activation and resolution in myeloid cells. (A) In the pro-inflammatory state, pathogen-associated molecular patterns or DAMPs activate TLR signaling via the MyD88–NF-κB axis, inducing transcription of pro-inflammatory cytokines. This state suppresses TREM2-mediated activation/phagocytosis. (B) Microglia engage TREM2–DAP12–SYK signaling upon sensing lipid-rich debris. This promotes phagocytosis, lipid processing in lysosomes, transcription of genes such as Apoe, Lpl, Axl, and Itgax, and generation of oxysterols, which activate LXR. (C) LXR activation promotes cholesterol efflux, inhibits NF-κB, and supports inflammation resolution. This pathway enables a transition to a reparative phenotype, maintaining TREM2 function and suppressing further inflammatory activation. SYK, spleen tyrosine kinase; MyD88, myeloid differentiation primary response gene 88.

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