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We previously developed a mouse model of two-stage laser-induced subretinal fibrosis that mimics closely the dynamic course of macular fibrosis in nAMD patients. This study was aimed to understand the molecular mechanism of subretinal fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Subretinal fibrosis was induced in C57BL\/6J mice using the two-stage laser-induced protocol. Twenty days later, eyes were collected and processed for RNA sequencing (RNA-seq) analysis. DESeq2 was used to determine the differentially expressed genes (DEGs). Gene Ontology (GO) and KEGG were used to analyze the enriched pathways. The expression of the selected DEGs including\n                      <jats:italic>Mmp12<\/jats:italic>\n                      was verified by qPCR. The expression of MMP12 in subretinal fibrosis of mouse and nAMD donor eyes was examined by immunofluorescence and confocal microscopy. The expression of collagen 1, \u03b1SMA and fibronectin and cytokines in bone marrow-derived macrophages from control and subretinal fibrosis mice were examined by qPCR, immunocytochemistry and Luminex multiplex cytokine assay. The MMP12 specific inhibitor MMP408 was used to evaluate the effect of MMP12 on TGF\u03b2-induced macrophage-to-myofibroblast transition (MMT) in vitro and its role in subretinal fibrosis in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RNA-seq analysis of RPE-choroid from subretinal fibrosis eyes uncovered 139 DEGs (fold change\u2009log2(fc)\u2009\u2265\u20090.5, FDR\u2009&lt;\u20090.05), including 104 up-regulated and 35 were down-regulated genes. The top 25 enrichment GO terms were related to inflammation, blood vessels\/cardiovascular development and angiogenesis. One of the most significantly upregulated genes,\n                      <jats:italic>Mmp12<\/jats:italic>\n                      , contributed to 12 of the top 25 GO terms. Higher levels of MMP12 were detected in subretinal fibrotic lesions in nAMD patients and the mouse model, including in\u00a0F4\/80\n                      <jats:sup>+<\/jats:sup>\n                      or Iba1\n                      <jats:sup>+<\/jats:sup>\n                      macrophages. BMDMs from subretinal fibrosis mice expressed higher levels of MMP12, collagen-1, \u03b1SMA and fibronectin. MMP408 dose-dependently suppressed TGF\u03b2-induced MMT in BMDMs. In vivo treatment with MMP408 (5\u00a0mg\/kg) significantly reduced subretinal fibrosis accompanied by reduced F4\/80\n                      <jats:sup>+<\/jats:sup>\n                      macrophage infiltration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>MMP12 critically contributes to the development of subretinal fibrosis, partially through promoting MMT.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-022-02433-x","type":"journal-article","created":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T09:10:45Z","timestamp":1649149845000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis"],"prefix":"10.1186","volume":"19","author":[{"given":"Caijiao","family":"Yi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heping","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,5]]},"reference":[{"issue":"10153","key":"2433_CR1","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","volume":"392","author":"P Mitchell","year":"2018","unstructured":"Mitchell P, Liew G, Gopinath B, Wong TY. 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