Ticam2, also known as TRAM, is an adaptor protein in the TLR signaling pathways. It plays a crucial role in mediating immune responses, as TLRs are key danger-sensing receptors that trigger inflammatory and anti-microbial responses. The protein is involved in the TRIF-dependent signaling cascade after TLR4 endocytosis, which is important for the regulation of pro-inflammatory responses [4].

Ticam2-deficient neutrophils have decreased expression of inflammatory adhesion molecules (such as ICAM1, CD11b) and immune-suppressors (like PD-L1), and reduced aggregation following prolonged LPS challenge, indicating its role in neutrophil exhaustion. Ticam2-deficient mice are protected from severe systemic inflammation and multi-organ injury after chemical-induced mucosal damage [1]. In a sepsis model, Ticam2 -/- mice showed that monocytes largely resembled healthy controls after one week of recovery, while wild-type monocytes remained persistently exhausted, suggesting Ticam2 contributes to the chronic preservation of monocyte exhaustion [2]. Ticam2 -/- mice were also highly susceptible to SARS-CoV infection, with increased weight loss and more pulmonary hemorrhage, highlighting its role in SARS-CoV disease [3].

In conclusion, Ticam2 is essential in regulating immune cell exhaustion and responses in various disease conditions. Gene-knockout mouse models, such as Ticam2 -/- mice, have been instrumental in revealing its role in neutrophil and monocyte exhaustion, as well as in diseases like severe systemic inflammation, sepsis, and SARS-CoV infection. Understanding Ticam2's functions can provide potential therapeutic approaches for these diseases.

References:

1. Lin, RuiCi, Zhang, Yao, Pradhan, Kisha, Li, Liwu. 2020. TICAM2-related pathway mediates neutrophil exhaustion. In Scientific reports, 10, 14397. doi:10.1038/s41598-020-71379-y. https://pubmed.ncbi.nlm.nih.gov/32873853/

2. Caldwell, Blake A, Ie, Susanti, Lucas, Amy, Li, Liwu. 2025. Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis. In Scientific reports, 15, 2059. doi:10.1038/s41598-025-86103-x. https://pubmed.ncbi.nlm.nih.gov/39814939/

3. Gralinski, Lisa E, Menachery, Vineet D, Morgan, Andrew P, Ferris, Martin T, Baric, Ralph S. 2017. Allelic Variation in the Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus Pathogenesis in Mice. In G3 (Bethesda, Md.), 7, 1653-1663. doi:10.1534/g3.117.041434. https://pubmed.ncbi.nlm.nih.gov/28592648/

4. Luo, Lin, Lucas, Richard M, Liu, Liping, Stow, Jennifer L. 2019. Signalling, sorting and scaffolding adaptors for Toll-like receptors. In Journal of cell science, 133, . doi:10.1242/jcs.239194. https://pubmed.ncbi.nlm.nih.gov/31889021/