LRRC8A, also known as SWELL1, is a key component of volume-regulated anion channels (VRACs). VRACs play a crucial role in regulating cell volume, which is essential for various cellular processes such as cell survival, growth, and proliferation [4]. The channels are involved in multiple biological pathways, including those related to immune cell activation, inflammation, and tumor progression. Genetic models, like gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying LRRC8A's functions.

In T cells, deletion of LRRC8A impairs cell activation and function, especially under weak TCR stimulation, suggesting that LRRC8A-controlled cell volume regulation is required for optimal T cell activation [1]. In microglia/macrophage (M/Mφ) cells, conditional knockout of Lrrc8a accelerates hematoma clearance, reduces neuronal death, and improves functional recovery after intracerebral hemorrhagic stroke by promoting M/Mφ phagocytosis [2]. In myofibroblasts, specific knockout of LRRC8A greatly attenuates myofibroblast transformation, fibrotic remodeling, and ventricular dysfunction after myocardial infarction [3].

In conclusion, LRRC8A is essential for regulating cell volume and is involved in multiple biological processes. KO/CKO mouse models have revealed its significance in diseases such as T-cell-related immune responses, intracerebral hemorrhagic stroke, and myocardial infarction-induced cardiac fibrosis. Understanding LRRC8A's functions provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Wang, Yuman, Sun, Zaiqiao, Ping, Jieming, Yin, Lei, Wu, Ning. 2023. Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function. In Nature communications, 14, 7075. doi:10.1038/s41467-023-42817-y. https://pubmed.ncbi.nlm.nih.gov/37925509/

2. Liu, Jing, Shen, Danmin, Wei, Chao, Yang, Fei, Li, Qian. 2022. Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke. In iScience, 25, 105527. doi:10.1016/j.isci.2022.105527. https://pubmed.ncbi.nlm.nih.gov/36465125/

3. Chen, Xiyao, Zhang, Fuyang, Hu, Guangyu, Wang, Ning, Wang, Xiaoming. 2022. LRRC8A critically regulates myofibroblast phenotypes and fibrotic remodeling following myocardial infarction. In Theranostics, 12, 5824-5835. doi:10.7150/thno.75200. https://pubmed.ncbi.nlm.nih.gov/35966575/

4. Kunzelmann, Karl. 2015. TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca(2+) and cell volume. In Trends in biochemical sciences, 40, 535-43. doi:10.1016/j.tibs.2015.07.005. https://pubmed.ncbi.nlm.nih.gov/26254230/