Acute and chronic injuries are characterized by leukocyte infiltration into tissues. Although matrix metalloproteinase 9 (Mmp9) has been implicated in both conditions, its role in wound repair remains unclear. We previously reported a zebrafish chronic inflammation mutant caused by an insertion in the hepatocyte growth factor activator inhibitor gene 1 (hai1; also known as spint1) that is characterized by epithelial extrusions and neutrophil infiltration into the fin. Here, we performed a microarray analysis and found increased inflammatory gene expression in the mutant larvae, including a marked increase in mmp9 expression. Depletion of mmp9 partially rescued the chronic inflammation and epithelial phenotypes, in addition to restoring collagen fiber organization, as detected by second-harmonic generation imaging. Additionally, we found that acute wounding induces epithelial cell mmp9 expression and is associated with a thickening of collagen fibers. Interestingly, depletion of mmp9 impaired this collagen fiber reorganization. Moreover, mmp9 depletion impaired tissue regeneration after tail transection, implicating Mmp9 in acute wound repair. Thus, Mmp9 regulates both acute and chronic tissue damage and plays an essential role in collagen reorganization during wound repair.
Funding
This work was supported by the National Institutes of Health [GM074827 and GM102924 to A.H.] and by the European Commission [LSHG-2006-037220 to A.Z. and A.H.M.]. Further support came from the Laboratory for Optical and Computational Instrumentation (LOCI) and support from the UW-UWM Intercampus research program (to K.W.E.). Deposited in PMC for release after 12 months.
Author contributions
D.C.L. performed most of the experiments, collected and analyzed data, prepared figures and wrote the manuscript. J.M.S. performed the SHG imaging and revised the manuscript. J.R. performed the in situ hybridization and isolated RNA for the microarray analysis. E.B. assisted the performing of experiments and collection of data. Y.L. developed the program for analysis of SHG imaging. A.Z. performed the microarray analysis. K.W.E. advised on the imaging, imaging study design and computational analysis. A.H. contributed to data analysis and co-wrote the manuscript.
