Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; School of Clinical Medicine, Faculty of Medicine, The University of Queensland, Brisbane, Australia.
School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia.
Mol Immunol. 2018 Sep;101:176-181. doi: 10.1016/j.molimm.2018.06.271. Epub 2018 Jun 27.
The complement system of innate immunity is emerging as a novel player in neurodevelopmental processes. The receptor for C3a, C3aR, shares a close evolutionary and functional relationship with C5a receptors. Whilst the C5a receptor, C5aR1, has been demonstrated to promote embryonic neural stem cell proliferation, little is known about the role of C3aR in this process. Here we show that C3aR is expressed in a similar manner to C5aR1 in mice, at the apical pole of the embryonic ventricular zone, though it has an opposing function. Using in utero delivery of C3aR agonist and antagonist compounds to the embryonic ventricle, we demonstrate that C3aR functions to decrease proliferation of apical neural progenitor cells (NPC). Intriguingly, C3aR animals also have altered NPC proliferation, but demonstrate an opposing phenotype to animals subjected to pharmacological blockade of C3aR. Finally, despite a grossly normal development of C3aR animals, cognitive behavioural testing of adult mice showed subtle deficits in recall memory. These data demonstrate that in addition to C5a, C3a also has a critical role in the normal development of the mammalian brain.
先天免疫系统的补体系统正在成为神经发育过程中的一个新角色。C3a 的受体 C3aR 与 C5a 受体在进化和功能上有着密切的关系。虽然 C5a 受体 C5aR1 已被证明能促进胚胎神经干细胞的增殖，但关于 C3aR 在这一过程中的作用知之甚少。在这里，我们发现在小鼠中，C3aR 的表达方式与 C5aR1 相似，位于胚胎脑室区的顶端，但它具有相反的功能。我们通过向胚胎脑室中递送 C3aR 激动剂和拮抗剂化合物，证明 C3aR 可减少顶端神经祖细胞 (NPC) 的增殖。有趣的是，C3aR 动物的 NPC 增殖也发生了改变，但表现出与 C3aR 药理学阻断动物相反的表型。最后，尽管 C3aR 动物的发育总体正常，但对成年小鼠的认知行为测试显示，它们在回忆记忆方面存在细微缺陷。这些数据表明，除了 C5a 之外，C3a 也在哺乳动物大脑的正常发育中具有关键作用。
