Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis

Yi, Caijiao; Liu, Jian; Deng, Wen; Luo, Chang; Qi, Jinyan; Chen, Mei; Xu, Heping

doi:10.1186/s12974-022-02433-x

Cited by 31 publications

(26 citation statements)

References 47 publications

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“…Thus, CD11c + macrophages are necessary for CNV. It is likely that is occurs by stimulating a multimodal pro-angiogenic gene expression program including increased Vegfa expression directly, Galectin receptor-driven increased transforming growth factor beta and VEGF signaling (34), endothelial sprouting via Annexins (33), cytokine (via Il1b and Cxcr4) signaling (35,36), and Mmp12 stimulated fibrosis (37).…”

Section: Discussionmentioning

confidence: 99%

CD11c+ macrophages are proangiogenic and necessary for experimental choroidal neovascularization

Droho¹,

Rajesh²,

Cuda³

et al. 2023

JCI Insight

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Patients with neovascular AMD (nAMD) suffer vision loss from destructive angiogenesis, termed choroidal neovascularization (CNV). Macrophages are found in CNV lesions from nAMD patients. Additionally, Ccr2 -/mice, which lack classical monocyte-derived macrophages, show reduced CNV size. However, macrophages are highly diverse cells that can perform multiple functions. We performed single-cell RNA-sequencing on immune cells from wildtype and Ccr2 -/eyes to uncover macrophage heterogeneity during the laser-induced CNV mouse model of nAMD. We identified 12 macrophage clusters, including Spp1 + macrophages. Spp1 + macrophages were enriched from wildtype lasered eyes and expressed a pro-angiogenic transcriptome via multiple pathways, including vascular endothelial growth factor signaling, endothelial cell sprouting, cytokine signaling, and fibrosis. Additionally, Spp1 + macrophages expressed the marker CD11c, and CD11c + macrophages were increased by laser and present in CNV lesions. Finally, CD11c + macrophage depletion reduced CNV size by 40%. These findings broaden our understanding of ocular macrophage heterogeneity and implicate CD11c + macrophages as a potential therapeutic target for treatment-resistant nAMD patients.

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Section: Discussionmentioning

confidence: 99%

CD11c+ macrophages are proangiogenic and necessary for experimental choroidal neovascularization

Droho¹,

Rajesh²,

Cuda³

et al. 2023

JCI Insight

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“…Recently, emerging evidence has demonstrated that bone marrow-derived macrophages can undergo a direct transition to myofibroblasts, which are principal collagen-producing cells that contribute to tissue fibrosis. [8][9][10][11][12] The researchers identified that nearly 50% of myofibroblasts originated from bone marrowderived macrophages in tissue fibrosis and named this process macrophage-myofibroblast transition (MMT). [11] Additionally, nearly 80% of MMT cells originate from the M2 subpopulation.…”

Section: Introductionmentioning

confidence: 99%

Antifibrotic Effects of Tetrahedral Framework Nucleic Acids by Inhibiting Macrophage Polarization and Macrophage–Myofibroblast Transition in Bladder Remodeling

Wang

Xiao

Lin

et al. 2023

Adv Healthcare Materials

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Bladder outlet obstruction (BOO) is a prevalent condition arising from urethral stricture, posterior urethral valves, and benign prostatic hyperplasia. Long‐term obstruction can lead to bladder remodeling, which is characterized by inflammatory cell infiltration, detrusor hypertrophy, and fibrosis. Until now, there are no efficacious therapeutic options for BOO‐induced remodeling. Tetrahedral framework nucleic acids (tFNAs) are a type of novel 3D DNA nanomaterials that possess excellent antifibrotic effects. Here, to determine the treatment effects of tFNAs on BOO‐induced remodeling is aimed. Four single‐strand DNAs are self‐assembled to form tetrahedral framework DNA nanostructures, and the antifibrotic effects of tFNAs are investigated in an in vivo BOO animal model and an in vitro transforming growth factor beta1 (TGF‐β1)‐induced fibrosis model. The results demonstrated that tFNAs could ameliorate BOO‐induced bladder fibrosis and dysfunction by inhibiting M2 macrophage polarization and the macrophage–myofibroblast transition (MMT) process. Furthermore, tFNAs regulate M2 polarization and the MMT process by deactivating the signal transducer and activator of transcription (Stat) and TGF‐β1/small mothers against decapentaplegic (Smad) pathways, respectively. This is the first study to reveal that tFNAs might be a promising nanomaterial for the treatment of BOO‐induced remodeling.

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“…Subretinal fibrosis was induced in young (2.5-month) and aged (15–16-month) mice using the two-stage laser protocol [ 26 , 27 ]. Lesions were examined 30 days after the second laser in RPE/choroid flatmounts (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…After induction of subretinal fibrosis, the expression of Acta2 and Fn1 was significantly increased in BMDM from young [ 27 ] and aged mice (Fig. 4 E), but the expression of Fn1 in BMDMs from aged subretinal fibrosis mice was significantly higher than that from young subretinal fibrosis mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A two-stage laser protocol detailed previously by us [ 26 , 27 ] was used to induce subretinal fibrosis in young (2.5–3 months or 4 months in BMT study) and aged (15–16 months and 24 months in BMT) mice. Briefly, mice were anaesthetized with an intraperitoneal injection of sodium pentobarbital (60 mg/kg, Sigma Aldrich, St. Louis, MO), and pupils were dilated with 0.5% tropicamide and 0.5% phenylephrine (Santen Pharmaceutical Co., Ltd., Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

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Old age promotes retinal fibrosis in choroidal neovascularization through circulating fibrocytes and profibrotic macrophages

Liu

Deng

et al. 2023

J Neuroinflammation

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Background Retinal fibrosis affects 40–70% of neovascular age-related macular degeneration patients. This study investigated the effect of ageing on subretinal fibrosis secondary to choroidal neovascularization and the mechanism of action. Methods Subretinal fibrosis was induced in young (2.5-month) and aged (15–16-month) C57BL/6J mice using the two-stage laser protocol. Five and 30 days later, eyes were collected and stained for CD45 and collagen-1 and observed by confocal microscopy. Fibrocytes (CD45+collagen-1+) were detected in the bone marrow (BM), blood and fibrotic lesions by flow cytometry and confocal microscopy, respectively. BM-derived macrophages (BMDMs) were cultured from young and aged mice with or without TGF-β1 (10 ng/mL) treatment. The expression of mesenchymal marker αSMA (Acta2), fibronectin (Fn1) and collagen-1 (Col1a1) was examined by qPCR and immunocytochemistry, whereas cytokine/chemokine production was measured using the Luminex multiplex cytokine assay. BM were transplanted from 22-month (Ly5.2) aged mice into 2.5-month (Ly5.1) young mice and vice versa. Six weeks later, subretinal fibrosis was induced in recipient mice and eyes were collected for evaluation of fibrotic lesion size. Results Under normal conditions, the number of circulating fibrocytes (CD45+collagen-1+) and the expression levels of Tgfb1, Col1a1, Acta2 and Fn1 in BMDMs were significantly higher in aged mice compared to young mice. Induction of subretinal fibrosis significantly increased the number of circulating fibrocytes, enhanced the expression of Col1a1, Acta2 and Fn1 and the production of soluble urokinase plasminogen activator surface receptor (suPAR) but decreased the production of CXCL10 in BMDMs. BMDMs from aged subretinal fibrosis mice produced significantly higher levels of VEGF, angiopoietin-2 and osteopontin than cells from young subretinal fibrosis mice. The subretinal fibrotic lesion in 15–16-month aged mice was 62% larger than that in 2.5-month young mice. The lesion in aged mice contained a significantly higher number of fibrocytes compared to that in young mice. The number of circulating fibrocytes positively correlated with the size of subretinal fibrotic lesion. Transplantation of BM from aged mice significantly increased subretinal fibrosis in young mice. Conclusions A retina–BM–blood–retina pathway of fibrocyte/macrophage recruitment exists during retinal injury. Ageing promotes subretinal fibrosis through higher numbers of circulating fibrocytes and profibrotic potential of BM-derived macrophages.

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Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis

Cited by 31 publications

References 47 publications

CD11c+ macrophages are proangiogenic and necessary for experimental choroidal neovascularization

CD11c+ macrophages are proangiogenic and necessary for experimental choroidal neovascularization

Antifibrotic Effects of Tetrahedral Framework Nucleic Acids by Inhibiting Macrophage Polarization and Macrophage–Myofibroblast Transition in Bladder Remodeling

Old age promotes retinal fibrosis in choroidal neovascularization through circulating fibrocytes and profibrotic macrophages

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