In Vivo Silencing of the Transcription Factor IRF5 Reprograms the Macrophage Phenotype and Improves Infarct Healing

Courties, Gabriel; Heidt, Timo; Sebas, Matthew; Iwamoto, Yoshiko; Jeon, Derrick; Truelove, Jessica; Tricot, Benoit; Wojtkiewicz, Gregory R.; Dutta, Partha; Sager, Hendrik B.; Borodovsky, Anna; Novobrantseva, Tatiana; Klebanov, Boris; Fitzgerald, Kevin; Anderson, Daniel G.; Libby, Peter; Świrski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias

doi:10.1016/j.jacc.2013.11.023

Cited by 231 publications

(201 citation statements)

References 40 publications

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“…Much attention has focused on vascular abnormalities in the pathogenesis of the delayed wound healing in diabetes (36)(37)(38). The observation that GM3S SNA treatment almost doubles CD31…”

Section: Discussionmentioning

confidence: 99%

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

Randeria

Seeger²,

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

197

163

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Spherical nucleic acid (SNA) gold nanoparticle conjugates (13-nmdiameter gold cores functionalized with densely packed and highly oriented nucleic acids) dispersed in Aquaphor have been shown to penetrate the epidermal barrier of both intact mouse and human skin, enter keratinocytes, and efficiently down-regulate gene targets. ganglioside-monosialic acid 3 synthase (GM3S) is a known target that is overexpressed in diabetic mice and responsible for causing insulin resistance and impeding wound healing. GM3S SNAs increase keratinocyte migration and proliferation as well as insulin and insulin-like growth factor-1 (IGF1) receptor activation under both normo-and hyperglycemic conditions. The topical application of GM3S SNAs (50 nM) to splinted 6-mm-diameter full-thickness wounds in diet-induced obese diabetic mice decreases local GM3S expression by >80% at the wound edge through an siRNA pathway and fully heals wounds clinically and histologically within 12 d, whereas control-treated wounds are only 50% closed. Granulation tissue area, vascularity, and IGF1 and EGF receptor phosphorylation are increased in GM3S SNA-treated wounds. These data capitalize on the unique ability of SNAs to naturally penetrate the skin and enter keratinocytes without the need for transfection agents. Moreover, the data further validate GM3 as a mediator of the delayed wound healing in type 2 diabetes and support regional GM3 depletion as a promising therapeutic direction.f 27 million Americans diagnosed with type 2 diabetes (T2D), more than 6 million have chronic, nonhealing skin wounds, particularly on the plantar surface, leading to secondary bacterial infection and costing the healthcare system more than $25 billion (1, 2). In 2010 alone, more than 70,000 individuals in the United States with T2D underwent amputation (3). Improved understanding of diabetic wound pathology and new interventions for impaired wound healing are needed.Ganglioside-monosialic acid 3 (GM3), the predominant sialylated glycosphingolipid in skin, has recently been recognized to be a critical mediator of insulin resistance (4-12). Indeed, we have recently shown three-and fourfold more GM3 synthase (GM3S; also known as SAT-I or ST3Gal-V), which is required for the synthesis of GM3, in diabetic human plantar skin than in site-and age-matched control skin (4). Similarly, skin samples from the backs of diet-induced obese (DIO) and ob/ob mouse diabetic models show increased GM3S mRNA expression and GM3 levels. Knockout (KO) of GM3S improves the insulin resistance induced by a high-fat diet in mouse adipose tissue, muscle (5), and as recently shown, skin of DIO T2D mice, reversing the woundhealing impairment of T2D (4). The acceleration of wound healing by GM3S KO and GM3 depletion in mouse skin is associated with increased epidermal cell migration and proliferation as well as activation of the epidermal insulin-like growth factor-1 receptor (IGF1R) in vivo (4). Isolated cultured mouse GM3S −/− keratinocytes (KCs) migrate and proliferate more rapidly than GM3S +/+ WT l...

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“…Much attention has focused on vascular abnormalities in the pathogenesis of the delayed wound healing in diabetes (36)(37)(38). The observation that GM3S SNA treatment almost doubles CD31…”

Section: Discussionmentioning

confidence: 99%

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

Randeria

Seeger²,

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

197

163

View full text Add to dashboard Cite

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“…The balance of M1 vs. M2 polarized macrophages has been shown to influence cardiac repair (56)(57)(58). Using rat and pig IR injury models, de Couto et al (59) showed that intracoronary infusion of CDC exosomes, but not inert fibroblast exosomes, reduced the number of CD68 + macrophages within infarcted tissue and modified the polarization state of macrophages.…”

Section: Macrophage Polarization By Cdc Exosomesmentioning

confidence: 99%

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

Barile¹,

Milano²,

Vassalli³

2017

Stem Cell Investig.

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When injected into acutely infarcted rodent or pig hearts, naturally secreted nanovesicles known as exosomes from cardiac-derived progenitor cells (CPCs) reduce scar size and improve cardiac function. In this regard, exosomes fully mimic the benefits of injecting their parent cells. This recognition paves the way to the development of exosome-based, cell-free treatments for heart disease that could possibly supplant cellbased therapies. Mechanisms of benefit of these vesicles are incompletely understood but cytoprotection, stimulation of angiogenesis, induction of antifibrotic cardiac fibroblasts, and modulation of M1/M2 polarization of macrophages infiltrating the infarcted region can all play important roles. Accordingly, the beneficial molecules carried by CPC-secreted exosomes have been identified only in part but cytoprotective and proangiogenic microRNAs (miRNA) and proteins have been described. Besides CPC-secreted exosomes, vesicles released from other cell types including mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iSPCs) have also been associated with cardioprotection. This review aims to discuss recent advances in our understanding of the role of secreted vesicles in cardiac repair, with a focus on CPC-derived exosomes.

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“…The continued dominance of M1 macrophages may accelerate and exacerbate ischemic infarction. 179 Courties et al 93 found that silencing IRF5 in M1 macrophages led to a strikingly suppressed progression of myocardial ischemia-induced necrosis and cardiac dysfunction caused by the downregulation of proinflammatory responses. These sophisticated molecular processes must be fully clarified.…”

Section: Interferon Regulatory Factormentioning

confidence: 99%

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

Zhang

2015

Hypertension

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In Vivo Silencing of the Transcription Factor IRF5 Reprograms the Macrophage Phenotype and Improves Infarct Healing

Cited by 231 publications

References 40 publications

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

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