C5ar1, the gene encoding the complement component 5a receptor 1, is a key player in the complement system. It binds to C5a, a pro-inflammatory anaphylatoxin, and is involved in various inflammatory pathways [5]. The C5a-C5aR1 axis is important in regulating immune responses, cell migration, and inflammation, with implications for multiple biological processes and disease states. Genetic models, such as KO or CKO mouse models, have been crucial in understanding its functions.

In a NASH mouse model, C5aR1 deletion reduced hepatic inflammation and fibrosis, with transcriptional profiling revealing enrichment of pathways like Toll-like receptor signaling [1]. In breast cancer, C5aR1 inhibition reprogrammed tumor-associated macrophages and reversed PARP inhibitor resistance [2]. In an Alzheimer's disease mouse model, the C5aR1 antagonist PMX205 improved outcomes, reduced neurotoxic astrocyte gene expression, and promoted signaling pathways related to cell growth and repair [3]. In lupus nephritis, knockdown of C5aR1 in podocytes suppressed C5a-C5aR1-controlled mitochondrial fission and podocyte injury [4].

In conclusion, C5aR1 is essential in regulating inflammation and immune-related processes. Model-based research, especially using KO/CKO mouse models, has revealed its significant roles in diseases such as NASH, breast cancer, Alzheimer's disease, and lupus nephritis. Understanding C5aR1 functions provides potential therapeutic targets for these diseases.

References:

1. Jiang, Keqing, Lu, Shibang, Li, Dongxiao, He, Songqing, Zhong, Fudi. 2023. Blockade of C5aR1 alleviates liver inflammation and fibrosis in a mouse model of NASH by regulating TLR4 signaling and macrophage polarization. In Journal of gastroenterology, 58, 894-907. doi:10.1007/s00535-023-02002-w. https://pubmed.ncbi.nlm.nih.gov/37227481/

2. Li, Xi, Poire, Alfonso, Jeong, Kang Jin, Sun, Chaoyang, Mills, Gordon B. 2024. C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer. In Nature communications, 15, 4485. doi:10.1038/s41467-024-48637-y. https://pubmed.ncbi.nlm.nih.gov/38802355/

3. Schartz, Nicole D, Liang, Heidi Y, Carvalho, Klebea, Mortazavi, Ali, Tenner, Andrea J. 2024. C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer's disease mouse model. In Nature communications, 15, 7028. doi:10.1038/s41467-024-51163-6. https://pubmed.ncbi.nlm.nih.gov/39147742/

4. Ye, Baokui, Chen, Binfeng, Guo, Chaohuan, Yang, Niansheng, Zhang, Hui. 2024. C5a-C5aR1 axis controls mitochondrial fission to promote podocyte injury in lupus nephritis. In Molecular therapy : the journal of the American Society of Gene Therapy, 32, 1540-1560. doi:10.1016/j.ymthe.2024.03.003. https://pubmed.ncbi.nlm.nih.gov/38449312/

5. Ruocco, Anna, Sirico, Anna, Novelli, Rubina, Aramini, Andrea, Amendola, Pier Giorgio. 2022. The role of C5a-C5aR1 axis in bone pathophysiology: A mini-review. In Frontiers in cell and developmental biology, 10, 957800. doi:10.3389/fcell.2022.957800. https://pubmed.ncbi.nlm.nih.gov/36003145/