Atypical chemokine receptor 3 (ACKR3, formerly CXC chemokine receptor 7) is a G protein-coupled receptor that recruits β-arrestins, but is devoid of functional G protein signaling after receptor stimulation. In preclinical models of liver and lung fibrosis, ACKR3 was previously shown to be upregulated after acute injury in liver sinusoidal and pulmonary capillary endothelial cells, respectively. This upregulation was linked with a pro-regenerative and anti-fibrotic role for ACKR3. A recently described ACKR3-targeting small molecule agonist protected mice from isoproterenol-induced cardiac fibrosis. Here, we aimed to evaluate its protective role in preclinical models of liver and lung fibrosis. After confirming its in vitro pharmacological activity (i.e., ACKR3-mediated β-arrestin recruitment and receptor binding), in vivo administration of this ACKR3 agonist led to increased mouse CXCL12 plasma levels, indicating in vivo interaction of the agonist with ACKR3. Whereas twice daily in vivo administration of the ACKR3 agonist lacked inhibitory effect on bleomycin-induced lung fibrosis, it had a modest, but significant anti-fibrotic effect in the carbon tetrachloride (CCl₄)-induced liver fibrosis model. In the latter model, ACKR3 stimulation affected the expression of several fibrosis-related genes and led to reduced collagen content as determined by picro-sirius red staining and hydroxyproline quantification. These data confirm that ACKR3 agonism, at least to some extent, attenuates fibrosis, although this effect is rather modest and heterogeneous across various tissue types. Stimulating ACKR3 alone without intervening in other signaling pathways involved in the multicellular crosstalk leading to fibrosis will, therefore, most likely not be sufficient to deliver a satisfactory clinical outcome.

非典型趋化因子受体 3（ACKR3，以前称为 CXC 趋化因子受体 7）是一种 G 蛋白偶联受体，可招募 β-抑制蛋白，但在受体刺激后缺乏功能性 G 蛋白信号传导。在肝纤维化和肺纤维化的临床前模型中，之前显示 ACKR3 在肝窦和肺毛细血管内皮细胞急性损伤后分别上调。这种上调与 ACKR3 的促再生和抗纤维化作用有关。最近描述的一种靶向 ACKR3 的小分子激动剂可以保护小鼠免受异丙肾上腺素诱导的心脏纤维化。在这里，我们的目的是评估其在肝和肺纤维化临床前模型中的保护作用。在确认其体外药理活性（即 ACKR3 介导的 β-arrestin 募集和受体结合）后，体内施用该 ACKR3 激动剂导致小鼠 CXCL12 血浆水平增加，表明该激动剂与 ACKR3 存在体内相互作用。虽然每天两次体内施用 ACKR3 激动剂对博来霉素诱导的肺纤维化缺乏抑制作用，但它在四氯化碳 (CCl ₄ ) 诱导的肝纤维化模型中具有适度但显着的抗纤维化作用。在后一种模型中，通过天狼星红染色和羟脯氨酸定量测定，ACKR3 刺激影响了几种纤维化相关基因的表达，并导致胶原蛋白含量减少。这些数据证实，ACKR3 激动剂至少在一定程度上减轻了纤维化，尽管这种作用相当温和且在不同组织类型中具有异质性。因此，仅刺激 ACKR3 而不干预参与导致纤维化的多细胞串扰的其他信号通路，很可能不足以提供令人满意的临床结果。