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* Laboratory of Development and Diseases and State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China;
Model Organism Division, E-Institutes of Shanghai Universities, Shanghai, China;
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115; and
¶ Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
Interstitial cell migration through extracellular matrix is a hallmark of the inflammation response, tumor invasion, and metastasis. We have established a stable zebrafish transgenic line expressing enhanced GFP under the lysozyme C promoter for visualizing and measuring primitive macrophage migration in vivo. We show that tissue-resident primitive macrophages migrate rapidly through extracellular matrix to the site of acute injury induced by tail transection. Mechanistically, the specific inhibition of JNK, but not p38 and ERK, dramatically abolished the chemotactic migration in a dose-dependent manner, suppressing the trauma-induced recruitment of phosphorylated C-Jun transcription factor to proximal AP-1 sites in the promoter of matrix metalloproteinase 13 (mmp13), a gene specifically expressed in primitive macrophages during embryogenesis and required for the interstitial migration. Furthermore, dexamethasone suppressed the trauma-induced JNK phosphorylation and macrophage migration accompanied by simultaneous up-regulation of mkp-1, a well-known phosphatase capable of inactivating phosphorylated JNK. The results indicate that the JNK-Mmp13 signaling pathway plays an essential role in regulating the innate immune cell migration in response to severe injury in vivo.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Basic Research Program of China (2007CB947003), National Natural Science Foundation of China (30525019), Hundred Scholars Award of Chinese Academy of Science (T.X.L.), Chinese National High Tech Program 863 (2006AA02A405), Chinese National Key Program for Basic Research 973 (2004CB518600), and the Key Discipline Program of Shanghai Municipal Education Commission (Y0201).
2 Address correspondence and reprint requests to Dr. Ting Xi Liu, Laboratory of Development and Diseases, Institute of Health Sciences, Room 408, Building 1, 225 South Chong Qing Road, Shanghai, 200025 China. E-mail address: txliu{at}sibs.ac.cn or Dr. Sai-Juan Chen, State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, RuiJin Hospital, 197 RuiJin Road II, Shanghai, 200025 China. E-mail address: sjchen{at}stn.sh.cn
3 Abbreviations used in this paper: ECM, extracellular matrix; MMP, matrix metalloproteinase; hpf, h post fertilization; E-ChIP, cmbryonic chromatin immunoprecipitation; EGFP, enhanced GFP; ICM, intermediate cell mass; p-JNK, JNK phosphorylation; hptt, hours post tail-transection; DN-JNK, dominant-negative JNK; dex, dexamethasone; GR, glucocorticoid receptor.
4 The online version of this article contains supplemental material.
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