Research Centre for Integrative Physiology & Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.
Drug Research Doctoral Programme (DRDP), University of Turku, Turku, Finland.
Front Immunol. 2021 Nov 19;12:774013. doi: 10.3389/fimmu.2021.774013. eCollection 2021.
Melanocortin receptor 1 (MC1-R) is expressed in leukocytes, where it mediates anti-inflammatory actions. We have previously observed that global deficiency of MC1-R signaling perturbs cholesterol homeostasis, increases arterial leukocyte accumulation and accelerates atherosclerosis in apolipoprotein E knockout (Apoe) mice. Since various cell types besides leukocytes express MC1-R, we aimed at investigating the specific contribution of leukocyte MC1-R to the development of atherosclerosis. For this purpose, male Apoe mice were irradiated, received bone marrow from either female Apoe mice or MC1-R deficient Apoe mice (Apoe Mc1r) and were analyzed for tissue leukocyte profiles and atherosclerotic plaque phenotype. Hematopoietic MC1-R deficiency significantly elevated total leukocyte counts in the blood, bone marrow and spleen, an effect that was amplified by feeding mice a cholesterol-rich diet. The increased leukocyte counts were largely attributable to expanded lymphocyte populations, particularly CD4 T cells. Furthermore, the number of monocytes was elevated in Apoe Mc1r chimeric mice and it paralleled an increase in hematopoietic stem cell count in the bone marrow. Despite robust leukocytosis, atherosclerotic plaque size and composition as well as arterial leukocyte counts were unaffected by MC1-R deficiency. To address this discrepancy, we performed an homing assay and found that MC1-R deficient CD4 T cells and monocytes were preferentially entering the spleen rather than homing in peri-aortic lymph nodes. This was mechanistically associated with compromised chemokine receptor 5 (CCR5)-dependent migration of CD4 T cells and a defect in the recycling capacity of CCR5. Finally, our data demonstrate for the first time that CD4 T cells also express MC1-R. In conclusion, MC1-R regulates hematopoietic stem cell proliferation and tissue leukocyte counts but its deficiency in leukocytes impairs cell migration a CCR5-dependent mechanism.
黑素皮质素受体 1（MC1-R）在白细胞中表达，在那里它介导抗炎作用。我们之前观察到，MC1-R 信号的全局缺失会扰乱胆固醇稳态，增加动脉白细胞积累并加速载脂蛋白 E 敲除（Apoe）小鼠的动脉粥样硬化。由于除白细胞以外的各种细胞类型都表达 MC1-R，我们旨在研究白细胞 MC1-R 对动脉粥样硬化发展的具体贡献。为此，雄性 Apoe 小鼠接受辐射，接受来自雌性 Apoe 小鼠或 MC1-R 缺陷 Apoe 小鼠（Apoe Mc1r）的骨髓，并分析组织白细胞谱和动脉粥样硬化斑块表型。造血 MC1-R 缺乏显著增加了血液、骨髓和脾脏中的总白细胞计数，这种效应因给小鼠喂食富含胆固醇的饮食而放大。白细胞计数的增加主要归因于淋巴细胞群体的扩大，特别是 CD4 T 细胞。此外，Apoe Mc1r 嵌合小鼠的单核细胞数量增加，与骨髓中造血干细胞计数的增加平行。尽管存在明显的白细胞增多，但 MC1-R 缺乏对动脉粥样硬化斑块大小和组成以及动脉白细胞计数没有影响。为了解决这一差异，我们进行了归巢实验，发现 MC1-R 缺陷型 CD4 T 细胞和单核细胞优先进入脾脏，而不是归巢到主动脉旁淋巴结。这在机制上与 CD4 T 细胞的趋化因子受体 5（CCR5）依赖性迁移受损和 CCR5 回收能力缺陷有关。最后，我们的数据首次表明 CD4 T 细胞也表达 MC1-R。总之，MC1-R 调节造血干细胞增殖和组织白细胞计数，但白细胞中的缺乏会损害细胞迁移——一种 CCR5 依赖性机制。
