Ccr2, the C-C chemokine receptor type 2, is a key receptor in the chemokine signaling network. It is mainly associated with the CCL2-CCR2 signaling axis, which plays a crucial role in various biological processes such as cell migration, immune cell recruitment, and inflammation regulation [1,2,3,4,5,6,7,8,9]. This axis is involved in multiple physiological and pathological conditions, highlighting its overall biological importance. Genetic models, like gene knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying Ccr2's function.

In cancer, blocking the CCL2/CCR2 axis with CCR2 knockout or a CCR2 antagonist inhibits malignant growth, metastasis, and postsurgical recurrence in murine HCC models, activating an antitumorous CD8+ T cell response, indicating its role in tumor progression [7]. In cardiovascular diseases, while laboratory data on the CCL2-CCR2 axis show promise, its clinical translation remains challenging [2]. In pulmonary hypertension, deleting Ccr2 in macrophages or pulmonary-artery smooth muscle cells (PASMCs) attenuates the growth response, and dual targeting of CCR2 and CCR5 is more effective in treating PH in mice [3]. In orthodontic tooth movement, blocking CCR2 significantly reduces the progression, revealing its role in alveolar bone remodeling [4]. In chronic headache, Ccr2 global knockout mice do not show acute or persistent facial skin hypersensitivity induced by repeated nitroglycerin administration, suggesting that CCL2-CCR2 signaling in macrophages and T cells contributes to chronic headache-related sensitization [6]. In osteoarthritis, Ccr2-deficient mice are protected against OA with a reduction in local monocyte/macrophage numbers in their joints, and blocking CCL2/CCR2 signalling attenuates macrophage accumulation, synovitis, and cartilage damage in mouse OA [9].

In conclusion, Ccr2, through the CCL2-CCR2 axis, is essential in regulating cell migration, immune cell recruitment, and inflammation. KO/CKO mouse models have revealed its significant roles in cancer, cardiovascular diseases, pulmonary hypertension, orthodontic tooth movement, chronic headache, and osteoarthritis. These findings contribute to our understanding of disease mechanisms and may offer potential therapeutic targets for these conditions.

References:

1. Xu, Maosen, Wang, Yang, Xia, Ruolan, Wei, Yuquan, Wei, Xiawei. 2021. Role of the CCL2-CCR2 signalling axis in cancer: Mechanisms and therapeutic targeting. In Cell proliferation, 54, e13115. doi:10.1111/cpr.13115. https://pubmed.ncbi.nlm.nih.gov/34464477/

2. Zhang, Haixia, Yang, Ke, Chen, Feng, Li, Lan, Fan, Guanwei. 2022. Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications. In Frontiers in immunology, 13, 975367. doi:10.3389/fimmu.2022.975367. https://pubmed.ncbi.nlm.nih.gov/36110847/

3. Abid, Shariq, Marcos, Elisabeth, Parpaleix, Aurélien, Adnot, Serge, Lipskaia, Larissa. 2019. CCR2/CCR5-mediated macrophage-smooth muscle cell crosstalk in pulmonary hypertension. In The European respiratory journal, 54, . doi:10.1183/13993003.02308-2018. https://pubmed.ncbi.nlm.nih.gov/31320454/

4. Xu, Hao, Zhang, Shuting, Sathe, Adwait Amod, Zhang, Hanwen, Yan, Bin. 2022. CCR2+ Macrophages Promote Orthodontic Tooth Movement and Alveolar Bone Remodeling. In Frontiers in immunology, 13, 835986. doi:10.3389/fimmu.2022.835986. https://pubmed.ncbi.nlm.nih.gov/35185928/

5. Li, Lan, Cao, Jiasong, Li, Sheng, Zhu, Meifeng, Fan, Guanwei. 2023. M2 Macrophage-Derived sEV Regulate Pro-Inflammatory CCR2+ Macrophage Subpopulations to Favor Post-AMI Cardiac Repair. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2202964. doi:10.1002/advs.202202964. https://pubmed.ncbi.nlm.nih.gov/36950739/

6. Ryu, Sun, Liu, Xuemei, Guo, Tingting, Zhang, Jintao, Cao, Yu-Qing. . Peripheral CCL2-CCR2 signalling contributes to chronic headache-related sensitization. In Brain : a journal of neurology, 146, 4274-4291. doi:10.1093/brain/awad191. https://pubmed.ncbi.nlm.nih.gov/37284790/

7. Li, Xiaoguang, Yao, Wenbo, Yuan, Ya, Jiang, Xiaoqing, Wang, Hui. 2015. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. In Gut, 66, 157-167. doi:10.1136/gutjnl-2015-310514. https://pubmed.ncbi.nlm.nih.gov/26452628/

8. Pozzi, Sabina, Satchi-Fainaro, Ronit. 2024. The role of CCL2/CCR2 axis in cancer and inflammation: The next frontier in nanomedicine. In Advanced drug delivery reviews, 209, 115318. doi:10.1016/j.addr.2024.115318. https://pubmed.ncbi.nlm.nih.gov/38643840/

9. Raghu, Harini, Lepus, Christin M, Wang, Qian, Sokolove, Jeremy B, Robinson, William H. 2016. CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis. In Annals of the rheumatic diseases, 76, 914-922. doi:10.1136/annrheumdis-2016-210426. https://pubmed.ncbi.nlm.nih.gov/27965260/