Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation

Wight, Thomas N.; Kang, Inkyung; Evanko, Stephen P.; Harten, Ingrid A.; Chang, Matthew S.; Pearce, Oliver M.T.; Allen, Carys E.; Frevert, Charles W.

doi:10.3389/fimmu.2020.00512

Cited by 168 publications

(148 citation statements)

References 201 publications

(260 reference statements)

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“…There is emerging evidence that V0/V1 versican synthesis and remodelling is closely associated with cellular processes necessary for effective regenerative myogenesis and driving the pathogenesis of DMD. This includes satellite cell proliferation 29 , myoblast fusion and myofibre formation 22 , and modulation of inflammatory responses [30][31][32] . By binding cytokines, chemokines and growth factors, such as TGFβ and monocyte chemoattractant protein-1 (MCP-1) 30 , versican CS side chains have important effects on cell signalling and behaviour 23 .…”

Section: Rermentioning

confidence: 99%

Genetic reduction of the extracellular matrix protein versican attenuates inflammatory cell infiltration and improves contractile function in dystrophic mdx diaphragm muscles

McRae

Addinsall

Howlett

et al. 2020

Sci Rep

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There is a persistent, aberrant accumulation of V0/V1 versican in skeletal muscles from patients with Duchenne muscular dystrophy and in diaphragm muscles from mdx mice. Versican is a provisional matrix protein implicated in fibrosis and inflammation in various disease states, yet its role in the pathogenesis of muscular dystrophy is not known. Here, female mdx and male hdf mice (haploinsufficient for the versican allele) were bred. In the resulting F1 mdx-hdf male pups, V0/V1 versican expression in diaphragm muscles was decreased by 50% compared to mdx littermates at 20-26 weeks of age. In mdx-hdf mice, spontaneous physical activity increased by 17% and there was a concomitant decrease in total energy expenditure and whole-body glucose oxidation. Versican reduction improved the ex vivo strength and endurance of diaphragm muscle strips. these changes in diaphragm contractile properties in mdx-hdf mice were associated with decreased monocyte and macrophage infiltration and a reduction in the proportion of fibres expressing the slow type I myosin heavy chain isoform. Given the high metabolic cost of inflammation in dystrophy, an attenuated inflammatory response may contribute to the effects of versican reduction on whole-body metabolism. Altogether, versican reduction ameliorates the dystrophic pathology of mdx-hdf mice as evidenced by improved diaphragm contractile function and increased physical activity. Abbreviations ½ RT ½ Relaxation time ADAMTS A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs CK Creatine kinase CS Chondroitin sulphate DAPC Dystropin-associated protein complex ECM Extracellular matrix GAG Glycosaminoglycan Lo Optimal length MCP-1 Macrophage chemoattractant protein-1

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Section: Rermentioning

confidence: 99%

Genetic reduction of the extracellular matrix protein versican attenuates inflammatory cell infiltration and improves contractile function in dystrophic mdx diaphragm muscles

McRae

Addinsall

Howlett

et al. 2020

Sci Rep

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“…Additionally, from 1 to 3dpp, the co-localization of F4/80 + cells with decorin and versican is parallel to the previous register of increased levels of pro-inflammatory mediators in interpubic tissues 36 and the upregulation DEGs related to macrophage activation in our microarray analysis. Keeping in mind that in its soluble form, digested ECM becomes potent DAMPs acting as immunomodulators 32,33 , our results strongly suggest that decorin and versican interact with IpL macrophage and influence their pro-inflammatory activation during fast IpL ECM degradation and PS histoarchitecture. Furthermore, macrophage co-localization with versican can also indicate that these cells produce versican in IpL, a process associated with macrophage maturation and activation in vitro 44,49 .…”

Section: Discussionmentioning

confidence: 61%

“…At postpartum, the co-localization between decorin, versican or HA with F4/80 + cells was simultaneous with the highest MMP2 protein levels detailed here and the formerly reported constant gene expression of Hyal1 and Hyal2 in IpL 8 , suggesting that these ECM elements may also be cleaved at postpartum. MMP2 activity may release decorin and versican from the ECM to act as endogenous ligands of TLRs at macrophage, triggering sterile inflammation by enhancing the synthesis of the pro-inflammatory cytokines [31][32][33] . Interestingly, from D18 to D19, when F4/80 + cells co-localized with versican, both the presence of pro-inflammatory macrophages (F4/80 + /CD40 + ) 36 and high levels of NO, a marker of M1 activity 47 , were found in the IpL 48 .…”

Section: Discussionmentioning

confidence: 99%

Evidence of macrophage modulation in the mouse pubic symphysis remodeling during the end of first pregnancy and postpartum

Castelucci

Pereira

Fioramonte

et al. 2020

Sci Rep

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pregnancy (D19) is due to the combined action of hormones and a wide variety of proteolytic enzymes, such as matrix metalloproteinases (Mmps), dipeptidyl peptidases (ADAMTs) and tissue inhibitor of metalloproteinases (Timps) and hyaluronidases (Hyals) 8,16. These molecules change the levels of proteoglycan, hyaluronic acid (HA), collagen, elastic fibers and water of IpL, leading to the increase in compliance and extendibility of this ligament before parturition 8-10,17. At IpL involution in postpartum, proteolytic enzymes and Hyals activity gradually decreased after 3dpp 8,16 , allowing bones and cartilage reformation by 10dpp to 40dpp at first pregnancy 12-14. Along with reproductive tissue remodeling, temporal changes in immune cell phenotypes reveal dynamic and multifaceted functions that are crucial to proper pregnancy development and successful labor 18-22. Among immune cells, macrophages are involved in a wide range of gestational processes, including regulation of immune cell activities, placental cell invasion, initiation of labor and postpartum reproductive organ remodeling 19,23-29. These cells show significant heterogeneity in function, majorly affected by their microenvironment. Under physiological conditions such as pregnancy connective tissue remodeling 30 , enzymatic breakdown of ECM components (proteoglycans and HA) produces soluble fragments that can act as damage-associated molecular patterns (DAMP). These endogenous signals trigger a fast macrophage response and interact with toll-like receptors (TLRs), leading to a sterile inflammation process to solve the adverse condition that initially led to DAMP release 31-33. Interestingly, aberrant modifications in the mouse reproductive tract or pelvic floor EMC molecules seem to be intimately associated with increased pro-inflammatory cytokine production in pelvic organs 34 and lead to exacerbated interpubic tissue relaxation for labor 15. In addition to recognizing the importance of immune cells in female reproductive tract modifications during pregnancy, studies showing immune cell involvement in PS remodeling in mice are scarce 12,14,20,35. Although neither neutrophils nor eosinophils are associated with this process 12,20,35 , recent data showed that both proinflammatory (M1) and anti-inflammatory (M2) activated macrophage phenotypes are present in the IpL from labor to early postpartum, suggesting that the differential gene expression of inflammatory mediators found in mouse interpubic tissues during this period may reflect IpL macrophage activities 36. Although significant PS ECM turnover gives rise to ECM fragments, it is still unknown whether macrophages interact with extracellular DAMPs or actively participate in IpL ECM remodeling for labor and postpartum recovery. The absence of mouse PS widening in the late stage of pregnancy leading to abnormal parturition and dystocia was observed in both genetically manipulated relaxin and relaxin receptor genes 37-39. Interestingly, a similar female mouse phenotype was also reported under combined abla...

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“…Additionally, during tissue inflammation, ECM proteins are degraded by proteases into bioactive matrix fragments, sometimes referred to as matrikines, which can have chemoattractant properties and pro-inflammatory effects similar to some cytokines [ 99 , 100 , 101 , 102 ]. Moreover, the ECM components hyaluronan and versican can bind to Toll-like receptors 2 and 4 to induce inflammatory gene expression in a variety of immune cells contributing to fueling inflammation at tumor sites [ 103 , 104 , 105 ]. Tumor-associated immunosuppressive cells secrete cytokines and other inflammatory mediators that support stemness properties, metastatic potential and tumorigenicity in CSCs [ 106 ].…”

Section: Cancer Stem Cell-derived Ecm Maintains Immune Evasionmentioning

confidence: 99%

Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded

Kesh

Gupta

Durden

et al. 2020

Cancers

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The extracellular matrix (ECM) has remained an enigmatic component of the tumor microenvironment. It drives metastasis via its interaction with the integrin signaling pathway, contributes to tumor progression and confers therapy resistance by providing a physical barrier around the tumor. The complexity of the ECM lies in its heterogeneous composition and complex glycosylation that can provide a support matrix as well as trigger oncogenic signaling pathways by interacting with the tumor cells. In this review, we attempt to dissect the role of the ECM in enriching for the treatment refractory cancer stem cell population and how it may be involved in regulating their metabolic needs. Additionally, we discuss how the ECM is instrumental in remodeling the tumor immune microenvironment and the potential ways to target this component in order to develop a viable therapy.

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Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation

Abstract: Frontiers in Immunology | www.frontiersin.org absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Cited by 168 publications

References 201 publications

Genetic reduction of the extracellular matrix protein versican attenuates inflammatory cell infiltration and improves contractile function in dystrophic mdx diaphragm muscles

Genetic reduction of the extracellular matrix protein versican attenuates inflammatory cell infiltration and improves contractile function in dystrophic mdx diaphragm muscles

Evidence of macrophage modulation in the mouse pubic symphysis remodeling during the end of first pregnancy and postpartum

Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded

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