Decorin Potentiates Interferon-γ Activity in a Model of Allergic Inflammation

Bocian, Carla; Urbanowitz, Ann-Kathrin; Owens, Rick T.; Iozzo, Renato V.; Götte, Martin; Seidler, Daniela G.

doi:10.1074/jbc.m112.419366

Cited by 28 publications

(30 citation statements)

References 67 publications

(65 reference statements)

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“…Decorin-TGF-β interactions can alter TGF-β intracellular signaling or cause TGF-β to become inactivated or sequestered in the ECM (Kolb et al, 2001); all of these scenarios would limit TGF-β-mediated glial scar formation and neutrophil chemotaxis. Conversely, the DS chain on decorin can enhance interferon-γ and TNF-α signaling (Bocian et al, 2013). Sulfated PGs also can control MMP localization and the ability of the enzyme to activate precursor proteins.…”

Section: Sulfated Proteoglycansmentioning

confidence: 99%

Extracellular matrix regulation of inflammation in the healthy and injured spinal cord

Gaudet

Popovich

2014

Experimental Neurology

173

133

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Throughout the body, the extracellular matrix (ECM) provides structure and organization to tissues and also helps regulate cell migration and intercellular communication. In the injured spinal cord (or brain), changes in the composition and structure of the ECM undoubtedly contribute to regeneration failure. Less appreciated is how the native and injured ECM influences intraspinal inflammation and, conversely, how neuroinflammation affects the synthesis and deposition of ECM after CNS injury. In all tissues, inflammation can be initiated and propagated by ECM disruption. Molecules of ECM newly liberated by injury or inflammation include hyaluronan fragments, tenascins, and sulfated proteoglycans. These act as “damage-associated molecular patterns” or “alarmins”, i.e., endogenous proteins that trigger and subsequently amplify inflammation. Activated inflammatory cells, in turn, further damage the ECM by releasing degradative enzymes including matrix metalloproteinases (MMPs). After spinal cord injury (SCI), destabilization or alteration of the structural and chemical composition of the ECM affects migration, communication, and survival of all cells – neural and non-neural – that are critical for spinal cord repair. By stabilizing ECM structure or modifying their ability to trigger the degradative effects of inflammation, it may be possible to create an environment that is more conducive to tissue repair and axon plasticity after SCI.

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Section: Sulfated Proteoglycansmentioning

confidence: 99%

Extracellular matrix regulation of inflammation in the healthy and injured spinal cord

Gaudet

Popovich

2014

Experimental Neurology

173

133

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“…Germane examples include immunomodulation [33,34], cutaneous wound healing [35], proper keratinocyte function [36], diabetic nephropathies [37], fetal membrane homeostasis [38], obesity and type II diabetes [39], allergen-induced asthma [40], allergic inflammation [41], delayed hypersensitivity reactions [42], hepatic fibrosis [43], myogenesis and muscular dystrophy [44,45], post myocardial infarction remodeling [46], and mediating proper vertebrate convergent extension [47]. Moreover, decorin has been identified as a potential biomarker for ischemic stroke [48], renal and pulmonary diseases [49-51] and for maintaining hematopoietic stem cell niches [52].…”

Section: Introductionmentioning

confidence: 99%

Decorin as a multivalent therapeutic agent against cancer

Neill

Schaefer

Iozzo

2016

Advanced Drug Delivery Reviews

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105

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Decorin is a prototypical small leucine-rich proteoglycan and epitomizes the multifunctional nature of this critical gene family. Soluble decorin engages multiple receptor tyrosine kinases within the target rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell mitophagy, and angiostasis. Decorin is also pro-inflammatory by modulating macrophage function and cytokine secretion. Decorin suppresses tumorigenic growth, angiogenesis, and prevents metastatic lesions in a variety of in vitro and in vivo tumor models. Therefore, decorin would be an ideal therapeutic candidate for combatting solid malignancies.

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“…Growth factors require GAGs for their function (Sarrazin et al, 2011) and DS can affect interferon-γ (Fernandez-Botran et al, 1999; Bocian et al, 2013) and fibroblast growth factors (FGFs) (Trowbridge et al, 2002; Taylor et al, 2005). In a contact allergy model, loss of decorin leads to a reduced edema formation due to a disturbed cytokine and chemokine expression profile (Seidler et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

A decorin-deficient matrix affects skin chondroitin/dermatan sulfate levels and keratinocyte function

et al. 2014

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Decorin is a small leucine-rich proteoglycan harboring a single glycosaminoglycan chain, which, in skin, is mainly composed of dermatan sulfate (DS). Mutant mice with targeted disruption of the decorin gene (Dcn−/−) exhibit an abnormal collagen architecture in the dermis and reduced tensile strength, collectively leading to a skin fragility phenotype. Notably, Ehlers-Danlos patients with mutations in enzymes involved in the biosynthesis of DS display a similar phenotype, and recent studies indicate that DS is involved in growth factor binding and signaling. To determine the impact of the loss of DS-decorin in the dermis, we analyzed the glycosaminoglycan content of Dcn−/− and wild-type mouse skin. The total amount of chondroitin/dermatan sulfate (CS/DS) was increased in the Dcn−/− skin, but was overall less sulfated with a significant reduction in bisulfated ΔDiS2,X (X=4 or 6) disaccharide units, due to the reduced expression of uronyl 2-O sulfotransferase (Ust). With increasing age, sulfation declined; however, Dcn−/− CS/DS was constantly undersulfated vis-à-vis wild-type. Functionally, we found altered fibroblast growth factor (Fgf)-7 and -2 binding due to changes in the micro-heterogeneity of skin Dcn−/− CS/DS. To better delineate the role of decorin, we used a 3D Dcn−/− fibroblast cell culture model. We found that the CS/DS extracts of wild-type and Dcn−/− fibroblasts were similar to the skin sugars, and this correlated with the lack of uronyl 2-O sulfotransferase in the Dcn−/− fibroblasts. Moreover, Ffg7 binding to total CS/DS was attenuated in the Dcn−/− samples. Surprisingly, wild-type CS/DS significantly reduced the binding of Fgf7 to keratinocytes in concentration dependent manner unlike the Dcn−/− CS/DS that only affected the binding at higher concentrations. Although binding to cell-surfaces was quite similar at higher concentrations, keratinocyte proliferation was differentially affected. Higher concentration of Dcn−/− CS/DS induced proliferation in contrast to wild-type CS/DS. 3D co-cultures of fibroblasts and keratinocytes showed that, unlike Dcn−/− CS/DS, wild-type CS/DS promoted differentiation of keratinocytes. Collectively, our results provide novel mechanistic explanations for the reported defects in wound healing in Dcn−/− mice and possibly Ehlers-Danlos patients. Moreover, the lack of decorin-derived DS and an altered CS/DS composition differentially influence keratinocyte behavior.

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Decorin Potentiates Interferon-γ Activity in a Model of Allergic Inflammation

Abstract: Background:The dermatan sulfate proteoglycan decorin modulates delayed-type hypersensitivity, leading to reduced edema. Results: Decorin deficiency leads to a reduced infiltration of CD8 ϩ leukocytes and deregulated cytokine expression. Decorin can

Cited by 28 publications

References 67 publications

Extracellular matrix regulation of inflammation in the healthy and injured spinal cord

Extracellular matrix regulation of inflammation in the healthy and injured spinal cord

Decorin as a multivalent therapeutic agent against cancer

A decorin-deficient matrix affects skin chondroitin/dermatan sulfate levels and keratinocyte function

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