Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype

Capote, Joana; Kramerova, Irina; Martinez, Leonel; Vetrone, Sylvia; Barton, Elisabeth R.; Sweeney, H. Lee; Miceli, M. Carrie; Spencer, Melissa J.

doi:10.1084/jem.2135oia35

Cited by 26 publications

(33 citation statements)

References 25 publications

(28 reference statements)

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“…However, this M1/M2 paradigm of MP activation appears oversimplified and does not fully explain the MP functional complexity seen in vivo (46,47). In the mdx mouse model, it has been shown that intramuscular MPs switched their phenotype from M1-like proinflammatory at 4 wk to M2-like proregenerative at 12 wk in the mdx leg muscles, which might contribute to the spontaneous improvement of leg muscle pathology at the late stages (48,49). To our knowledge, there has been no detailed study of functional phenotypes of MPs in mdx diaphragm.…”

Section: Discussionmentioning

confidence: 98%

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CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx ^5cv mice

et al. 2016

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Genetic ablation or pharmacologic inhibition of CC chemokine receptor type 2 (CCR2) reduced macrophage (MP) infiltration and improved muscle pathology and function in mdx diaphragm muscle at early stages. We addressed whether CCR2 deficiency resulted in sustained improvement of mdx-Ccr2 diaphragm. Compared to mdx controls, CCR2 deficiency in mdx-Ccr2 mice markedly reduced intramuscular Ly6C MPs at all stages, but it reduced Ly6C MPs only at early stages (4 and 9 wk). CCR2 deficiency reduced quadriceps and diaphragm muscle damage and fibrosis at 14 wk but not at 6 mo, and it improved diaphragm muscle regeneration and respiratory function at 14 wk but not at 6 mo. Intramuscular MPs in mdx-Ccr2 diaphragm expressed a low level of IL-1β, IL-6, and IFN-γ genes, a similar level of TNF-α, TGF-β1, and platelet-derived growth factor α genes, and a high level of IGF-1 and osteopontin genes compared to mdx controls. Diaphragm fibroblasts at 14 wk showed a similar cell number with a similar level of collagen and profibrogenic growth factor gene expression in mdx-Ccr2 and mdx mice. Diaphragm MPs from both mdx-Ccr2 and mdx mice stimulated collagen gene expression by cocultured fibroblasts. The findings suggest that CCR2 deficiency does not provide a sustained benefit and that Ly6C MPs may contribute to the progressive fibrosis and dysfunction of mdx diaphragm.-Zhao, W., Wang, X., Ransohoff, R. M., Zhou, L. CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx mice.

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Section: Discussionmentioning

confidence: 98%

“…Although the CCR2-deficient diaphragm MPs expressed a high level of IGF-1, which is a potent myotrophic growth factor, they also expressed a high level of OPN, which could reduce the M2c proregenerative function (48). IGF-1 can also play a fibrogenic role, depending on the tissue environment (51).…”

Section: Discussionmentioning

confidence: 99%

CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx ^5cv mice

et al. 2016

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“…Studies in mammals have described contradictory roles for OPN in controlling macrophage phenotype; it may be a marker of alternatively activated 'M2' macrophages in the mouse heart 24 but loss of OPN promotes a more anti-inflammatory phenotype in a model of muscular dystrophy. 51 We have used tnfa and spp1 expression to define macrophage activation state, but further investigation will be required to delineate the precise phenotypes of macrophage populations in the adult zebrafish heart and to determine differences from mammalian macrophages, perhaps further illustrating why scar removal is so much more effective in zebrafish than in mammals. spp1 2/2 fish exhibit reduced collagen deposition at 3 and 7 dpi but they exhibit significantly more scarring at 28 and 60 dpi when compared to wildtype fish, indicating a failure in resolution.…”

Section: Discussionmentioning

confidence: 99%

Specific macrophage populations promote both cardiac scar deposition and subsequent resolution in adult zebrafish

Bevan

Lim

Venkatesh

et al. 2019

Cardiovascular Research

168

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Aims A robust inflammatory response to tissue injury is a necessary part of the repair process but the deposition of scar tissue is a direct downstream consequence of this response in many tissues including the heart. Adult zebrafish not only possess the capacity to regenerate lost cardiomyocytes but also to remodel and resolve an extracellular scar within tissues such as the heart, but this scar resolution process remains poorly understood. This study aims to characterize the scarring and inflammatory responses to cardiac damage in adult zebrafish in full and investigate the role of different inflammatory subsets specifically in scarring and scar removal. Methods and results Using stable transgenic lines, whole organ imaging and genetic and pharmacological interventions, we demonstrate that multiple inflammatory cell lineages respond to cardiac injury in adult zebrafish. In particular, macrophage subsets (tnfα+ and tnfα−) play prominent roles with manipulation of different phenotypes suggesting that pro-inflammatory (tnfα+) macrophages promote scar deposition following cardiac injury whereas tnfα− macrophages facilitate scar removal during regeneration. Detailed analysis of these specific macrophage subsets reveals crucial roles for Csf1ra in promoting pro-inflammatory macrophage-mediated scar deposition. Additionally, the multifunctional cytokine Osteopontin (Opn) (spp1) is important for initial scar deposition but also for resolution of the inflammatory response and in late-stage ventricular collagen remodelling. Conclusions This study demonstrates the importance of a correctly balanced inflammatory response to facilitate scar deposition during repair but also to allow subsequent scar resolution, and full cardiac regeneration, to occur. We have identified Opn as having both pro-fibrotic but also potentially pro-regenerative roles in the adult zebrafish heart, driving Collagen deposition but also controlling inflammatory cell resolution.

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“…Moreover, we showed that Postn deficiency or antisense delivery against Postn were largely protective in CKD models leading to less inflammation and fibrosis (44). Induction of Postn was attributed to pro-inflammatory pathways, while its deleterious function was linked to activation of integrin signaling (45) (73,74).…”

Section: Periostinmentioning

confidence: 93%

Matricellular Proteins and Organ Fibrosis

Prakoura

Chatziantoniou

2017

Curr Pathobiol Rep

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Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype

Cited by 26 publications

References 25 publications

CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx ^5cv mice

CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx ^5cv mice

Specific macrophage populations promote both cardiac scar deposition and subsequent resolution in adult zebrafish

Matricellular Proteins and Organ Fibrosis

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Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype

Cited by 26 publications

References 25 publications

CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx 5cv mice

CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx 5cv mice

Specific macrophage populations promote both cardiac scar deposition and subsequent resolution in adult zebrafish

Matricellular Proteins and Organ Fibrosis

Contact Info

Product

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CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx ^5cv mice

CCR2 deficiency does not provide sustained improvement of muscular dystrophy in mdx ^5cv mice