Proinflammatory Signals and the Loss of Lymphatic Vessel Hyaluronan Receptor-1 (LYVE-1) in the Early Pathogenesis of Laminin Alpha2-deficient Skeletal Muscle

Wardrop, Katherine E.; Dominov, Janice A.

doi:10.1369/jhc.2010.956672

Cited by 13 publications

(27 citation statements)

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“…Another down-regulation of the hyaluronan receptor was noted in lymphatic vessels during the early stages 24-48 h after mycoplasma infection (11). LYVE-1 is also lost from sinusoidal endothelial cells of the liver during inflammation (1) and from lymphatic vessels in the early phase of some murine models accompanied with muscle degeneration and inflammation, possibly due to the induction of TNFα (20). On the other hand, high molecular weight hyaluronan modulates inflammatory responses in macrophages: it inhibits LPS-induced inflammatory signalings in macrophages and microglia (2,16,21,22).…”

Section: Lyve1mentioning

confidence: 99%

“…Although any direct interaction of hyaluronan with LYVE-1 is unknown, the loss of LYVE-1 in macrophagic cells of the mesentery may be involved in the activation of inflammatory responses. In fact, Wardrop and Dominov (20) described how the disappearance of LYVE-1 in lymphatic vessels provides a sensitive biomarker to monitor active inflammatory or tissue damages.…”

Section: Lyve1mentioning

confidence: 99%

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Three types of macrophagic cells in the mesentery of mice with special referenceto LYVE-1-immunoreactive cells

et al. 2014

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Immunohistochemistry using whole mount preparations of the murine mesentery revealed two types of LYVE-1-immunoreactive cells with dendritic morphology other than F4/80 + typical macrophages. The two types of LYVE-1 + cells were regularly distributed with constant intervals throughout the mesentery and appeared to possess their own territory. Both types of LYVE-1 + cells were weakly or moderately immunopositive for F4/80 antibody, a marker of macrophages, while F4/80 + round macrophages were absolutely free from the LYVE-1 immunoreactivity. Only macrophages could ingest latex particles of 20 nm in diameter 3 h after a peritoneal injection. Peritoneal administration of lipopolysaccharide (LPS) induced a rapid reduction of LYVE-1 immunoreactivity in the cells with dendritic morphology followed by an increased immunoreactivity to F4/80 antibody, and simultaneously by dynamic changes in their shape. Under normal conditions, F4/80 + macrophages in various connective tissues expressed LYVE-1, in contrast to lack of LYVE-1 in F4/80 + macrophages within the parenchyma of visceral organs and macrophages residing in hepatic sinusoids and pulmonary alveoli. LYVE-1 may play a role in cell adhesion and migration of macrophagic cells within connective tissues rich in hyaluronan, and loss of LYVE-1 becomes a reliable sign of activated conditions in inflammation.Membranous tissues such as the omentum and mesentery contain many macrophages and related cells, including Langerhans/dendritic cells. However, their distinct classification and functions remain unclear. As shown by their stainability with marker antibodies and enzymatic activities, cells with dendritic morphology in the rat omentum were very close to Ia antigen-positive interdigitating cells of lymphatic tissues (9). This study also noted that cells with dendritic morphology in the rat omentum were fairly heterogeneous (9). Zhu et al. (23) recognized the stellate or dendritic cells in the mouse omentum to be scavenging macrophages due to their phagocytic activity, stainability to marker antibodies, and severe reduction in number in op/op mice.

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Section: Lyve1mentioning

confidence: 99%

Section: Lyve1mentioning

confidence: 99%

Three types of macrophagic cells in the mesentery of mice with special referenceto LYVE-1-immunoreactive cells

et al. 2014

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“…macrophage) infiltration and loss of LYVE-1 [7]. Death mechanisms related to the proinflammatory environment present within a week after birth could play a prominent role in the initial muscle loss in this disease.…”

Section: Discussionmentioning

confidence: 97%

“…Using a Lama2 -deficient mouse model ( Lama2 dy-W [6]), we found that expression of the proinflammatory cytokines TNFα and IL-1β is elevated in Lama2 -mutant muscles within 7 days after birth, prior to widespread muscle degeneration [7]. Lama2 -deficient muscle also had increased expression of tenascin C (TN-C), a matrix glycoprotein upregulated in pathological conditions such as inflammation, as well as reduced expression of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in lymphatic capillaries within the muscles [7].…”

Section: Introductionmentioning

confidence: 99%

“…Lama2 -deficient muscle also had increased expression of tenascin C (TN-C), a matrix glycoprotein upregulated in pathological conditions such as inflammation, as well as reduced expression of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in lymphatic capillaries within the muscles [7]. LYVE-1 is specifically found in lymphatic endothelial cells and is rapidly degraded when these cells are exposed to TNFα [8], therefore changes in both TN-C and LYVE-1 could result from elevated inflammatory cytokines present in 7 day-old Lama2 -deficient muscles.…”

Section: Introductionmentioning

confidence: 99%

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Bcl-2 Inhibits the Innate Immune Response during Early Pathogenesis of Murine Congenital Muscular Dystrophy

et al. 2011

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Laminin α2 (LAMA2)-deficient congenital muscular dystrophy is a severe, early-onset disease caused by abnormal levels of laminin 211 in the basal lamina leading to muscle weakness, transient inflammation, muscle degeneration and impaired mobility. In a Lama2-deficient mouse model for this disease, animal survival is improved by muscle-specific expression of the apoptosis inhibitor Bcl-2, conferred by a MyoD-hBcl-2 transgene. Here we investigated early disease stages in this model to determine initial pathological events and effects of Bcl-2 on their progression. Using quantitative immunohistological and mRNA analyses we show that inflammation occurs very early in Lama2-deficient muscle, some aspects of which are reduced or delayed by the MyoD-hBcl-2 transgene. mRNAs for innate immune response regulators, including multiple Toll-like receptors (TLRs) and the inflammasome component NLRP3, are elevated in diseased muscle compared with age-matched controls expressing Lama2. MyoD-hBcl-2 inhibits induction of TLR4, TLR6, TLR7, TLR8 and TLR9 in Lama2-deficient muscle compared with non-transgenic controls, and leads to reduced infiltration of eosinophils, which are key death effector cells. This congenital disease model provides a new paradigm for investigating cell death mechanisms during early stages of pathogenesis, demonstrating that interactions exist between Bcl-2, a multifunctional regulator of cell survival, and the innate immune response.

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A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides

Dominov

Uyan

Sapp

et al. 2014

Ann Clin Transl Neurol

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ObjectiveMutations in dysferlin (DYSF), a Ca2+-sensitive ferlin family protein important for membrane repair, vesicle trafficking, and T-tubule function, cause Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal myopathy. More than 330 pathogenic DYSF mutations have been identified within exons or near exon–intron junctions. In ~17% of patients who lack normal DYSF, only a single disease-causing mutation has been identified. We studied one family with one known mutant allele to identify both the second underlying genetic defect and potential therapeutic approaches.MethodsWe sequenced the full DYSF cDNA and investigated antisense oligonucleotides (AONs) as a tool to modify splicing of the mRNA transcripts in order to process out mutant sequences.ResultsWe identified a novel pseudoexon between exons 44 and 45, (pseudoexon 44.1, PE44.1), which inserts an additional 177 nucleotides into the mRNA and 59 amino acids within the conserved C2F domain of the DYSF protein. Two unrelated dysferlinopathy patients were also found to carry this mutation. Using AONs targeting PE44.1, we blocked the abnormal splicing event, yielding normal, full-length DYSF mRNA, and increased DYSF protein expression.InterpretationThis is the first report of a deep intronic mutation in DYSF that alters mRNA splicing to include a mutant peptide fragment within a key DYSF domain. We report that AON-mediated exon-skipping restores production of normal, full-length DYSF in patients’ cells in vitro, offering hope that this approach will be therapeutic in this genetic context, and providing a foundation for AON therapeutics targeting other pathogenic DYSF alleles.

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Proinflammatory Signals and the Loss of Lymphatic Vessel Hyaluronan Receptor-1 (LYVE-1) in the Early Pathogenesis of Laminin Alpha2-deficient Skeletal Muscle

Cited by 13 publications

References 50 publications

Three types of macrophagic cells in the mesentery of mice with special referenceto LYVE-1-immunoreactive cells

Three types of macrophagic cells in the mesentery of mice with special referenceto LYVE-1-immunoreactive cells

Bcl-2 Inhibits the Innate Immune Response during Early Pathogenesis of Murine Congenital Muscular Dystrophy

A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides

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