MyD88, the myeloid differentiation primary response protein 88, is a key adaptor protein in innate immune signaling. It is central to inflammatory pathways as it links IL-1 receptor (IL-1R) or Toll-like receptor (TLR) family members to IL-1R-associated kinase (IRAK) family kinases via protein-protein interaction. This activation leads to the activation of pathways like nuclear factor-kappa B (NFκB), mitogen-activated protein kinases, and activator protein 1 [1].

MyD88-KO mouse models have revealed its significance in multiple biological processes. In trained immunity, MyD88-dependent signaling is crucial for TLR-mediated induction of trained immunity in macrophages, as MPLA-induced resistance to Staphylococcus aureus infection is lost in MyD88-KO mice [2]. In liver fibrosis, MyD88 deficiency in quiescent or activated hepatic stellate cells attenuates liver fibrosis, inhibits cell activation, and reduces inflammatory cell infiltration and pro-inflammatory gene expression [3]. In colorectal cancer, knockdown of MyD88 in cell lines and in a nude mouse model suppressed cell growth, invasion, and migration, affecting the MyD88-NF-κB/AP-1 signaling pathways [4].

In conclusion, MyD88 is essential for innate immune and inflammatory signaling. Gene knockout models, especially MyD88-KO mouse models, have been instrumental in demonstrating its role in diseases such as infections, liver fibrosis, and colorectal cancer, providing valuable insights into disease mechanisms and potential therapeutic targets.

References:

1. Deguine, Jacques, Barton, Gregory M. 2014. MyD88: a central player in innate immune signaling. In F1000prime reports, 6, 97. doi:10.12703/P6-97. https://pubmed.ncbi.nlm.nih.gov/25580251/

2. Owen, Allison M, Luan, Liming, Burelbach, Katherine R, Sherwood, Edward R, Bohannon, Julia K. 2022. MyD88-dependent signaling drives toll-like receptor-induced trained immunity in macrophages. In Frontiers in immunology, 13, 1044662. doi:10.3389/fimmu.2022.1044662. https://pubmed.ncbi.nlm.nih.gov/36439136/

3. Zhang, Jie, Liu, Yu, Chen, Haiqiang, Gu, Jianchun, Zhang, Jinhua. 2022. MyD88 in hepatic stellate cells enhances liver fibrosis via promoting macrophage M1 polarization. In Cell death & disease, 13, 411. doi:10.1038/s41419-022-04802-z. https://pubmed.ncbi.nlm.nih.gov/35484116/

4. Zhu, Guangwei, Cheng, Zhibin, Huang, Yongjian, Lin, Chunlin, Ye, Jianxin. 2019. MyD88 mediates colorectal cancer cell proliferation, migration and invasion via NF‑κB/AP‑1 signaling pathway. In International journal of molecular medicine, 45, 131-140. doi:10.3892/ijmm.2019.4390. https://pubmed.ncbi.nlm.nih.gov/31746347/