PMID- 30616691 OWN - NLM STAT- MEDLINE DCOM- 20190415 LR - 20200225 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 16 IP - 1 DP - 2019 Jan 7 TI - Long-term characterization of activated microglia/macrophages facilitating the development of experimental brain metastasis through intravital microscopic imaging. PG - 4 LID - 10.1186/s12974-018-1389-9 [doi] LID - 4 AB - BACKGROUND: Microglia/macrophages (M/Ms) with multiple functions derived from distinct activation states are key surveillants maintaining brain homeostasis. However, their activation status and role during the brain metastasis of malignant tumors have been poorly characterized. METHODS: Heterozygous CX3CR1-GFP transgenic mice were used to visualize the dynamic changes of M/Ms during the development of experimental brain metastasis through long-term intravital imaging equipped with redesigned bilateral cranial windows. The occurrence of experimental brain metastasis was evaluated after M/Ms were depleted with PLX3397, a CSF-1R inhibitor. The possible mediators of M/Ms in facilitating the brain metastasis were determined using reverse transcription-PCR, immunofluorescence, correlational analysis, and MMP inhibition. RESULTS: Here, we showed that M/Ms were persistently activated and facilitated the formation of melanoma brain metastasis in vivo. We observed that M/Ms gradually and massively accumulated in the metastasis, with a 2.89-fold increase. To precisely depict the dynamic changes in the activation state of M/Ms, we defined the branching parameter to quantify their morphological alterations. The quantitative data showed that the extent of activation of M/Ms in metastatic foci was enhanced, with a 2.27-fold increase from day 1 to day 21. Along with the activation, the M/Ms increased their moving velocity (4.15-fold) and established a rapid, confined, and discontinuous motility behavior. The occurrence of melanoma brain metastasis was significantly hindered under M/M elimination, indicating the key role of M/Ms in the experimental brain metastasis. Interestingly, we found that M/Ms highly expressed matrix metalloproteinase 3 (MMP3), which were strongly correlated with M/M activation and the decrease of tight junction protein zonula occludens-1 (ZO-1). An MMP inhibitor moderately decreased the occurrence of melanoma brain metastasis, suggesting that MMP3 secreted by M/Ms may facilitate melanoma cell growth. CONCLUSIONS: Our results indicated that the activated M/Ms were essential in the development of melanoma brain metastasis, suggesting that M/Ms are a potential therapeutic target for tumor brain metastasis. FAU - Qiao, Sha AU - Qiao S AD - Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Room G304, Wuhan, 430074, Hubei, China. AD - MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China. FAU - Qian, Yuan AU - Qian Y AD - Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Room G304, Wuhan, 430074, Hubei, China. AD - MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China. FAU - Xu, Guoqiang AU - Xu G AD - Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Room G304, Wuhan, 430074, Hubei, China. AD - MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China. FAU - Luo, Qingming AU - Luo Q AD - Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Room G304, Wuhan, 430074, Hubei, China. AD - MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China. FAU - Zhang, Zhihong AU - Zhang Z AUID- ORCID: 0000-0001-5227-8926 AD - Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Room G304, Wuhan, 430074, Hubei, China. czyzzh@mail.hust.edu.cn. AD - MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China. czyzzh@mail.hust.edu.cn. LA - eng GR - 81625012/the National Science Fund for Distinguished Young Scholars/ GR - 61721092/the Science Fund for Creative Research Groups of the National Natural Science Foundation of China/ GR - 2015ZDTD014, 2018KFYXKJC040/the Fundamental Research Funds for the Central Universities/ PT - Journal Article DEP - 20190107 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Aminopyridines) RN - 0 (CX3C Chemokine Receptor 1) RN - 0 (Cx3cr1 protein, mouse) RN - 0 (Pyrroles) RN - 0 (Tjp1 protein, mouse) RN - 0 (Zonula Occludens-1 Protein) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 6783M2LV5X (pexidartinib) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) SB - IM MH - Aminopyridines/administration & dosage MH - Animals MH - Brain/*diagnostic imaging/metabolism/pathology MH - Brain Neoplasms/*diagnostic imaging/*pathology/secondary MH - CX3C Chemokine Receptor 1/genetics/metabolism MH - Cell Line, Tumor MH - Disease Models, Animal MH - Functional Laterality MH - Gene Expression Regulation, Neoplastic/genetics/*physiology MH - Green Fluorescent Proteins/genetics/metabolism MH - Intravital Microscopy/methods MH - Macrophages/drug effects/metabolism/*pathology MH - Matrix Metalloproteinase 3/genetics/metabolism MH - Melanoma/pathology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Microglia/drug effects/metabolism/*pathology MH - Pyrroles/administration & dosage MH - Time Factors MH - Zonula Occludens-1 Protein/genetics/metabolism PMC - PMC6323850 OTO - NOTNLM OT - Activation OT - Intravital imaging OT - MMP3 OT - Melanoma brain metastasis OT - Microglia/macrophage COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All animal studies were conducted in compliance with protocols approved by the Hubei Provincial Animal Care and Use Committee and in compliance with the experimental guidelines of the Animal Experimentation Ethics Committee of Huazhong University of Science and Technology. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/01/09 06:00 MHDA- 2019/04/16 06:00 PMCR- 2019/01/07 CRDT- 2019/01/09 06:00 PHST- 2018/05/28 00:00 [received] PHST- 2018/12/11 00:00 [accepted] PHST- 2019/01/09 06:00 [entrez] PHST- 2019/01/09 06:00 [pubmed] PHST- 2019/04/16 06:00 [medline] PHST- 2019/01/07 00:00 [pmc-release] AID - 10.1186/s12974-018-1389-9 [pii] AID - 1389 [pii] AID - 10.1186/s12974-018-1389-9 [doi] PST - epublish SO - J Neuroinflammation. 2019 Jan 7;16(1):4. doi: 10.1186/s12974-018-1389-9.