Decoding the role of Trem2 in infection-related diseases: ligands, functional mechanisms, and cellular pathways

Triggering receptor expressed on myeloid cells 2 (Trem2), as a pivotal phagocytic receptor, serves as an important regulator in immune responses and inflammation during infection. Here, we summarize the multifaceted functions of Trem2 on infection-related diseases, including its anti-inflammatory effects, enhancement of phagocytic activity, and promotion of cell maturation and survival. By integrating current evidence, this review examines Trem2–DAP12/DAP10 signaling, with particular attention to its interactions with TLR4 and its downstream PLCγ2 and PI3K pathways during pathogenic infections. Our assessment focuses on how pathogen species, cell type, and infection stage shape its divergent effects on the inflammation and host defense, paying particular attention to the distinction between pathogen uptake and intracellular killing. Despite its capacity to limit tissue damage, Trem2’s immunoregulatory roles can facilitate pathogen persistence as well. We distinguish mechanisms established in infection models from those inferred from non-infection contexts, and further considers the therapeutic potential and limitations of targeting Trem2 in infectious diseases.