In vivo interstitial migration of primitive macrophages mediated by JNK-matrix metalloproteinase 13 signaling in response to acute injury.
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.
Zhang
Yong
Y
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.
Bai
Xue-Tao
XT
Zhu
Kang-Yong
KY
Jin
Yi
Y
Deng
Min
M
Le
Huang-Ying
HY
Fu
Yan-Fang
YF
Chen
Yi
Y
Zhu
Jiang
J
Look
A Thomas
AT
Kanki
John
J
Chen
Zhu
Z
Chen
Sai-Juan
SJ
Liu
Ting Xi
TX
D000208:Acute Disease; D000818:Animals; D030801:Animals, Genetically Modified; D002465:Cell Movement / Q000187:drug effects; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology; D007422:Intestines / Q000166:cytology* / Q000196:embryology / Q000201:enzymology* / Q000293:injuries; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005938:Glucocorticoids; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; D053509:Matrix Metalloproteinase 13