Il23a-KO Mouse

Il23a, also known as interleukin 23 subunit alpha (p19), is a crucial subunit of the pro-inflammatory cytokine interleukin-23 (IL-23). IL-23 is composed of Il23a and IL-12/23B (p40), and it drives the differentiation and activation of T helper 17 (Th17) cells, which leads to the production of cytokines like IL-17A, IL-17F, IL-6, IL-22, and tumor necrosis factor α (TNF-α). The IL-23/IL-17 pathway plays a pivotal role in protective immune responses against bacterial and fungal infections, but its dysregulation exacerbates chronic immune-mediated inflammation [2].

Brain endothelial-specific ablation of Il23a ameliorated both microglia activation and cognitive dysfunction induced by bortezomib exposure. This suggests that the endothelial TFEB-STAT3-Il23A axis in the brain is a critical cellular event for initiating bortezomib-mediated aberrant microglial activation and synapse engulfment [3]. In psoriasis, CD14+ type 3 dendritic cells in lesional skin co-produce IL1B and Il23a, which are pathological in psoriasis [1]. Also, in inflammatory bowel disease, higher mucosal Il23a expression was associated with a greater likelihood of achieving remission with ustekinumab treatment [4].

In conclusion, Il23a is essential in the IL-23/IL-17 pathway, playing a role in both normal immune responses and the pathogenesis of various diseases. Gene-knockout studies, such as the brain endothelial-specific ablation of Il23a in mice, have revealed its role in microglia-related cognitive dysfunction. Its involvement in psoriasis and inflammatory bowel disease further emphasizes its importance in chronic inflammatory diseases, providing potential therapeutic targets for these conditions.

References:

1. Nakamizo, Satoshi, Dutertre, Charles-Antoine, Khalilnezhad, Ahad, Kabashima, Kenji, Ginhoux, Florent. 2021. Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis. In The Journal of experimental medicine, 218, . doi:10.1084/jem.20202345. https://pubmed.ncbi.nlm.nih.gov/34279540/

2. Schinocca, Claudia, Rizzo, Chiara, Fasano, Serena, Ciccia, Francesco, Guggino, Giuliana. 2021. Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview. In Frontiers in immunology, 12, 637829. doi:10.3389/fimmu.2021.637829. https://pubmed.ncbi.nlm.nih.gov/33692806/

3. Lu, Yaping, Chen, Xiang, Liu, Xiuxiu, Han, Feng, Lu, Ying-Mei. 2023. Endothelial TFEB signaling-mediated autophagic disturbance initiates microglial activation and cognitive dysfunction. In Autophagy, 19, 1803-1820. doi:10.1080/15548627.2022.2162244. https://pubmed.ncbi.nlm.nih.gov/36588318/

4. Nishioka, Kei, Ogino, Haruei, Chinen, Takatoshi, Nakamura, Kazuhiko, Ogawa, Yoshihiro. 2021. Mucosal IL23A expression predicts the response to Ustekinumab in inflammatory bowel disease. In Journal of gastroenterology, 56, 976-987. doi:10.1007/s00535-021-01819-7. https://pubmed.ncbi.nlm.nih.gov/34448069/