Massara Matteo, Bonavita Ornella, Savino Benedetta, Caronni Nicoletta, Mollica Poeta Valeria, Sironi Marina, Setten Elisa, Recordati Camilla, Crisafulli Laura, Ficara Francesca, Mantovani Alberto, Locati Massimo, Bonecchi Raffaella
Humanitas Clinical and Research Center, via Manzoni 56, 20089, Rozzano, MI, Italy.
Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Via Fratelli Cervi, 93, 20090, Segrate, MI, Italy.
Nat Commun. 2018 Feb 14;9(1):676. doi: 10.1038/s41467-018-03080-8.
Atypical chemokine receptors (ACKRs) are regulators of leukocyte traffic, inflammation, and immunity. ACKR2 is a scavenger for most inflammatory CC chemokines and is a negative regulator of inflammation. Here we report that ACKR2 is expressed in hematopoietic precursors and downregulated during myeloid differentiation. Genetic inactivation of ACKR2 results in increased levels of inflammatory chemokine receptors and release from the bone marrow of neutrophils with increased anti-metastatic activity. In a model of NeuT-driven primary mammary carcinogenesis ACKR2 deficiency is associated with increased primary tumor growth and protection against metastasis. ACKR2 deficiency results in neutrophil-mediated protection against metastasis in mice orthotopically transplanted with 4T1 mammary carcinoma and intravenously injected with B16F10 melanoma cell lines. Thus, ACKR2 is a key regulator (checkpoint) of mouse myeloid differentiation and function and its targeting unleashes the anti-metastatic activity of neutrophils in mice.
非典型趋化因子受体（ACKRs）是白细胞运输、炎症和免疫的调节因子。ACKR2是大多数炎性CC趋化因子的清除剂，是炎症的负调节因子。在此我们报告，ACKR2在造血前体细胞中表达，并在髓系分化过程中下调。ACKR2的基因失活导致炎性趋化因子受体水平升高，且具有增强抗转移活性的中性粒细胞从骨髓中释放。在NeuT驱动的原发性乳腺癌发生模型中，ACKR2缺陷与原发性肿瘤生长增加及转移保护相关。ACKR2缺陷导致在原位移植4T1乳腺癌并静脉注射B16F10黑色素瘤细胞系的小鼠中，中性粒细胞介导的转移保护作用。因此，ACKR2是小鼠髓系分化和功能的关键调节因子（检查点），其靶向作用可释放小鼠中性粒细胞的抗转移活性。
