C3ar1, the gene encoding the C3a receptor 1, is a crucial component of the complement system. C3aR1 binds to C3a, a product of complement activation, and this interaction mediates various inflammatory and immune-related processes. The C3a-C3aR1 axis has been implicated in multiple biological functions and disease-related pathways, highlighting its overall biological importance. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying its function [1,2,3,4].

In pancreatic β-cells, β-cell-specific C3ar1 knockout (β-C3aR1 KO) mice show worse glucose tolerance, lower insulin levels, decreased β-cell mass, and impaired insulin secretion. Disrupting C3ar1 on β-cells abolishes the insulin secretory response to C3a, establishing a C3a-C3aR1 signaling axis crucial for maintaining β-cell homeostasis, especially under the metabolic stress of obesity and type 2 diabetes (T2D) [1,5]. In Foxp3+ T regulatory cells, disabled C3ar1/C5ar1 signaling leads to Treg-specific demethylation region (TSDR) demethylation and long-term stability in C3ar1-/-C5ar1-/-Foxp3+ cells [2]. Male adipocyte-specific C3aR1-knockout mice exhibit enhanced white adipose tissue (WAT) thermogenesis, while female adipocyte-specific C3aR1-knockout mice display decreased brown fat thermogenesis, revealing sexual dimorphism in the adipsin/C3a/C3aR1 axis in regulating adipose thermogenesis [3]. In the context of paclitaxel-induced peripheral neuropathic pain, C3aR1 knockout mice show less severe mechanical allodynia, with paclitaxel inducing lower expression of transient receptor potential channels of the vanilloid subtype 4 (TRPV4) in dorsal root ganglion (DRG) neurons, suggesting C3aR1's role in upregulating TRPV4 and promoting DRG macrophage expansion [4].

In conclusion, C3ar1 plays essential roles in maintaining β-cell function and mass in T2D, regulating Treg stability, adipose thermogenesis in a sex-dependent manner, and contributing to paclitaxel-induced peripheral neuropathic pain. The use of C3ar1 KO/CKO mouse models has been pivotal in uncovering these functions in specific disease-related biological processes.

References:

1. de Lima, Renan Pereira, Li, Ang, Gilani, Ankit, Lo, James C. 2024. C3aR1 on β cells enhances β cell function and survival. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.11.11.622969. https://pubmed.ncbi.nlm.nih.gov/39605339/

2. Medof, M Edward, Rieder, Sadiye A, Shevach, Ethan M. . Disabled C3ar1/C5ar1 Signaling in Foxp3+ T Regulatory Cells Leads to TSDR Demethylation and Long-Term Stability. In Journal of immunology (Baltimore, Md. : 1950), 211, 1359-1366. doi:10.4049/jimmunol.2300184. https://pubmed.ncbi.nlm.nih.gov/37756526/

3. Ma, Lunkun, Gilani, Ankit, Rubio-Navarro, Alfonso, Tang, Liling, Lo, James C. 2024. Adipsin and adipocyte-derived C3aR1 regulate thermogenic fat in a sex-dependent fashion. In JCI insight, 9, . doi:10.1172/jci.insight.178925. https://pubmed.ncbi.nlm.nih.gov/38713526/

4. Xu, Jijun, Huang, Ping, Bie, Bihua, Cheng, Jianguo, Lin, Feng. . Complement Receptor C3aR1 Contributes to Paclitaxel-Induced Peripheral Neuropathic Pain in Mice and Rats. In Journal of immunology (Baltimore, Md. : 1950), 211, 1736-1746. doi:10.4049/jimmunol.2300252. https://pubmed.ncbi.nlm.nih.gov/37861348/

5. Pereira de Lima, Renan, Li, Ang, Gilani, Ankit, Geri, Jacob B, Lo, James C. 2025. C3aR1 on β cells enhances β cell function and survival to maintain glucose homeostasis. In Molecular metabolism, 96, 102134. doi:10.1016/j.molmet.2025.102134. https://pubmed.ncbi.nlm.nih.gov/40189102/