C5ar2, also known as C5L2 or GPR77, is a non-classical G-protein-coupled receptor that binds to the complement activation product C5a. It is involved in modulating innate and adaptive immunity, with the ability to mediate its own signaling events and influence other pattern recognition receptors and innate immune systems like NLRP3 inflammasomes [1]. C5ar2 is considered a key modulator of immune cell activity, potentially through β-arrestins rather than G-proteins [2].

In gene-knockout (KO) mouse models, C5ar2 deficiency has been shown to have various effects. In a peritonitis model, more neutrophils were present in C5ar2-/-peritoneal cavity, indicating C5aR2 antagonizes C5aR1 signal in neutrophil chemotaxis. Also, C5ar2-/-macrophages had reduced C5ar1 mRNA and protein expression, suggesting C5aR2 in macrophages may cooperate with C5aR1 inflammatory signals [3]. In murine epidermolysis bullosa acquisita, C5ar2-/-mice showed an attenuated disease phenotype, with C5ar2-/-neutrophils having reduced intracellular calcium flux, ROS release, and migratory capacity. C5aR2 deficiency also lowered the ratio of activating and inhibitory FcγRs, impeding inflammation [4]. Similar findings were seen in mice with LysM-specific deletion of C5aR2, where disease progression was ameliorated, and neutrophils lacking C5aR2 had decreased activation after C5a stimulation and increased expression of the inhibitory Fcγ receptor FcγRIIb [5]. In a mouse model of acute pyelonephritis, C5ar2-/-mice had significantly reduced renal inflammation, tubular damage, and renal bacterial load, with decreased intrarenal levels of HMGB1, NLRP3 inflammasome components, cleaved caspase-1, and IL-1β [6].

In conclusion, model-based research, especially through C5ar2 KO mouse models, has revealed that C5ar2 plays a role in neutrophil activation, chemotaxis, and the regulation of inflammatory responses in diseases such as epidermolysis bullosa acquisita and acute pyelonephritis. It also has an impact on the relationship between C5aR1 and immune cell function, highlighting its significance in immune-related disease mechanisms.

References:

1. Li, Xaria X, Lee, John D, Kemper, Claudia, Woodruff, Trent M. . The Complement Receptor C5aR2: A Powerful Modulator of Innate and Adaptive Immunity. In Journal of immunology (Baltimore, Md. : 1950), 202, 3339-3348. doi:10.4049/jimmunol.1900371. https://pubmed.ncbi.nlm.nih.gov/31160390/

2. Das, Aurosikha, Gupta, Pulkit K, Rana, Soumendra. 2022. C5aR2 receptor: The genomic twin of the flamboyant C5aR1. In Journal of cellular biochemistry, 123, 1841-1856. doi:10.1002/jcb.30320. https://pubmed.ncbi.nlm.nih.gov/35977039/

3. Zhang, Ting, Ma, Ning, Wang, Jiaxing, Wei, Linlin, Li, Ke. 2024. C5aR2 Deficiency Lessens C5aR1 Distribution and Expression in Neutrophils and Macrophages. In Journal of immunology research, 2024, 2899154. doi:10.1155/2024/2899154. https://pubmed.ncbi.nlm.nih.gov/39021433/

4. Seiler, Daniel Leonard, Kleingarn, Marie, Kähler, Katja Hendrika, Ludwig, Ralf J, Karsten, Christian Marcel. 2022. C5aR2 Deficiency Ameliorates Inflammation in Murine Epidermolysis Bullosa Acquisita by Regulating Fcγ Receptor Expression on Neutrophils. In The Journal of investigative dermatology, 142, 2715-2723.e2. doi:10.1016/j.jid.2021.12.029. https://pubmed.ncbi.nlm.nih.gov/35007559/

5. Seiler, Daniel L, Kähler, Katja H, Kleingarn, Marie, Ludwig, Ralf J, Karsten, Christian M. 2023. The complement receptor C5aR2 regulates neutrophil activation and function contributing to neutrophil-driven epidermolysis bullosa acquisita. In Frontiers in immunology, 14, 1197709. doi:10.3389/fimmu.2023.1197709. https://pubmed.ncbi.nlm.nih.gov/37275893/

6. Zhang, Ting, Wu, Kun-Yi, Ma, Ning, Zhou, Wuding, Li, Ke. 2020. The C5a/C5aR2 axis promotes renal inflammation and tissue damage. In JCI insight, 5, . doi:10.1172/jci.insight.134081. https://pubmed.ncbi.nlm.nih.gov/32191644/