TREM1, triggering receptor expressed on myeloid cells 1, is a cell surface receptor expressed on neutrophils, monocytes, and some tissue macrophages, functioning as an immunoregulator controlling myeloid cell responses. Its activation, mediated by ligands and structural multimerization, activates downstream signaling pathways that lead to the production of pro-inflammatory cytokines and chemokines, thus acting as an inflammation amplifier. It is involved in the pathogenesis of many inflammation-associated diseases [2].

In diabetes-associated cognitive impairment (DACI), genetic or pharmacological blockade of TREM1 with LP17 in db/db mice and HFD/STZ mice inhibited lipid droplets and TREM1 accumulation, reduced hippocampal neuronal inflammatory damage, and improved cognitive functions. This suggests that TREM1 accumulation in microglia due to impaired lipophagy promotes neuroinflammatory cascades in DACI [1]. In cancer, TREM1-deficient mice showed delayed tumor growth in melanoma and fibrosarcoma models. TREM1 deficiency decreased the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs), expanded cytotoxic CD8+ T cells, and enhanced the antitumorigenic effect of anti-PD-1 treatment [3].

In conclusion, TREM1 is a key regulator in inflammation-related processes. Through gene-knockout (KO) mouse models, its role in diseases such as DACI and cancer has been revealed. In DACI, it is involved in microglial-mediated neuroinflammation, and in cancer, it promotes an immunosuppressive tumor microenvironment. Understanding TREM1 through these models provides potential therapeutic targets for these diseases.

References:

1. Li, Qing, Zhao, Yujing, Guo, Hongyan, Wang, Nan, Wang, Qiang. 2023. Impaired lipophagy induced-microglial lipid droplets accumulation contributes to the buildup of TREM1 in diabetes-associated cognitive impairment. In Autophagy, 19, 2639-2656. doi:10.1080/15548627.2023.2213984. https://pubmed.ncbi.nlm.nih.gov/37204119/

2. Li, Chenyang, Cai, Chujun, Xu, Dafeng, Chen, Xiaoping, Song, Jia. 2024. TREM1: Activation, signaling, cancer and therapy. In Pharmacological research, 204, 107212. doi:10.1016/j.phrs.2024.107212. https://pubmed.ncbi.nlm.nih.gov/38749377/

3. Ajith, Ashwin, Mamouni, Kenza, Horuzsko, Daniel D, Trinchieri, Giorgio, Horuzsko, Anatolij. 2023. Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti-PD-1 resistance. In The Journal of clinical investigation, 133, . doi:10.1172/JCI167951. https://pubmed.ncbi.nlm.nih.gov/37651197/