Twist1 in Infiltrating Macrophages Attenuates Kidney Fibrosis via Matrix Metallopeptidase 13–Mediated Matrix Degradation
| Autor: | Jamie R. Privratsky, Jiafa Ren, Jiandong Zhang, Yi Wen, Xiaohan Lu, Michael D. Gunn, Nathan P. Rudemiller, Steven D. Crowley, Robert I. Griffiths |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
animal structures Chemistry medicine.medical_treatment Matrix metallopeptidase 13 General Medicine Proinflammatory cytokine Extracellular matrix 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Cytokine Interstitial matrix Nephrology 030220 oncology & carcinogenesis Renal fibrosis Cancer research medicine Macrophage Extracellular Matrix Degradation |
| Zdroj: | Journal of the American Society of Nephrology. 30:1674-1685 |
| ISSN: | 1533-3450 1046-6673 |
| Popis: | Background Following an acute insult, macrophages regulate renal fibrogenesis through the release of various factors that either encourage the synthesis of extracellular matrix synthesis or the degradation of matrix via endocytosis, proteolysis, or both. However, the roles of infiltrating versus resident myeloid cells in these opposing processes require elucidation. The transcription factor Twist1 controls diverse essential cellular functions through induction of several downstream targets, including matrix metalloproteinases (MMPs). In macrophages, Twist1 can influence patterns of cytokine generation, but the role of macrophage Twist1 in renal fibrogenesis remains undefined. Methods To study Twist1 functions in different macrophage subsets during kidney scar formation, we used two conditional mutant mouse models in which Twist1 was selectively ablated either in infiltrating, inflammatory macrophages or in resident tissue macrophages. We assessed fibrosis-related parameters, matrix metallopeptidase 13 (MMP13, or collagen 3, which catalyzes collagen degradation), inflammatory cytokines, and other factors in these Twist1-deficient mice compared with wild-type controls after subjecting the animals to unilateral ureteral obstruction. We also treated wild-type and Twist1-deficient mice with an MMP13 inhibitor after unilateral ureteral obstruction. Results Twist1 in infiltrating inflammatory macrophages but not in resident macrophages limited kidney fibrosis after ureteral obstruction by driving extracellular matrix degradation. Moreover, deletion of Twist1 in infiltrating macrophages attenuated the expression of MMP13 in CD11b+Ly6Clo myeloid cells. Inhibition of MMP13 abrogated the protection from renal fibrosis afforded by macrophage Twist1. Conclusions Twist1 in infiltrating myeloid cells mitigates interstitial matrix accumulation in the injured kidney by promoting MMP13 production, which drives extracellular matrix degradation. These data highlight the complex cell-specific actions of Twist1 in the pathogenesis of kidney fibrosis. |
| Databáze: | OpenAIRE |
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