Connexins and pannexins in the immune system and lymphatic organs

Glass, Aaron; Snyder, Elizabeth G.; Taffet, Steven M.

doi:10.1007/s00018-015-1966-3

Cited by 44 publications

(41 citation statements)

References 79 publications

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“…16 Under resting conditions, Cx43 hemichannels have a low open probability but in the presence of molecules recognizable by the innate immune system, the increased assembly and opening of hemichannels can be triggered to induce release of proinflammatory molecules and ATP. 13,16 It is likely that at least some of the cells that express Cx43 hemichannels and contribute to RPE activation of the inflammasome are resident macrophages, 12,13,71,72 further supporting that the intervention with Cx43MP is regulating inflammation. Intervention in the ischemia-reperfusion rat model using a Cx43 channel blocking mimetic peptide reduced the number of inflammatory cells in the tissue and restored retinal function.…”

Section: Discussionmentioning

confidence: 99%

Sustained Connexin43 Mimetic Peptide Release From Loaded Nanoparticles Reduces Retinal and Choroidal Photodamage

Nor

Guo

Rupenthal

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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Section: Discussionmentioning

confidence: 99%

Sustained Connexin43 Mimetic Peptide Release From Loaded Nanoparticles Reduces Retinal and Choroidal Photodamage

Nor

Guo

Rupenthal

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…S5), however, suggesting either a very early requirement for Cx43 in LECs or their precursors, before the Lyve-1 promoter is active, or that the Cx43 −/− -specific defects were due to the absence of Cx43 from a non-LEC cell-type. Cx43 is known to be expressed by mesenchymal stem cells, which can affect lymphangiogenesis (Valiunas et al, 2004; Buttler et al, 2013; Maertens et al, 2014), as well as macrophages and lymphocytes (Glass et al, 2015), which have been implicated in pathological lymphangiogenesis (Betterman and Harvey, 2016). In addition, Cx43 expression in thymic regulatory T cell precursors enhances the production of Foxp3 + regulatory T cells (Kuczma et al 2011), a population of cells which were recently shown to modulate lymphedema and promote lymphatic vessel function (Gousopoulos et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Munger

Davis

Simon

2017

Developmental Biology

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Lymphatic valves (LVs) are cusped luminal structures that permit the movement of lymph in only one direction and are therefore critical for proper lymphatic vessel function. Congenital valve aplasia or agenesis can, in some cases, be a direct cause of lymphatic disease. Knowledge about the molecular mechanisms operating during the development and maintenance of LVs may thus aid in the establishment of novel therapeutic approaches to treat lymphatic disorders. In this study, we examined the role of Connexin43 (Cx43), a gap junction protein expressed in lymphatic endothelial cells (LECs), during valve development. Mouse embryos with a null mutation in Cx43 (Gja1) were previously shown to completely lack mesenteric LVs at embryonic day 18. However, interpreting the phenotype of Cx43−/− mice was complicated by the fact that global deletion of Cx43 causes perinatal death due to heart defects during embryogenesis. We have now generated a mouse model (Cx43ΔLEC) with a lymphatic-specific ablation of Cx43 and show that the absence of Cx43 in LECs causes a delay (rather than a complete block) in LV initiation, an increase in immature valves with incomplete leaflet elongation, a reduction in the total number of valves, and altered lymphatic capillary patterning. The physiological consequences of these lymphatic changes were leaky valves, insufficient lymph transport and reflux, and a high incidence of lethal chylothorax. These results demonstrate that the expression of Cx43 is specifically required in LECs for normal development of LVs.

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“…Three other genes preferentially upregulated by SLR14 have been primarily characterized as neuronal proteins (Gje1, Cbln1, and Itpr1). Further investigation of these neuronal proteins revealed homology with known effectors of immune function (connexins, complement domains, and inositol receptors, respectively), which may suggest a bone fide role for these genes in the immune response (55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 95%

A minimal RNA ligand for potent RIG-I activation in living mice

Linehan

Dickey

Molinari

et al. 2017

Preprint

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We have developed highly potent synthetic activators of the vertebrate immune system that specifically target the RIG-I receptor. When introduced into mice, a family of short, triphosphorylated Stem Loop RNAs (SLRs) induces a potent interferon response and the activation of specific genes essential for antiviral defense. Using RNAseq, we provide the first in-vivo genome-wide view of the expression networks that are initiated upon RIG-I activation. We observe that SLRs specifically induce type I interferons, subsets of interferon-stimulated genes (ISGs), and cellular remodeling factors. By contrast, poly(I:C), which binds and activates multiple RNA sensors, induces type III interferons and several unique ISGs. The short length (10-14 base pairs) and robust function of SLRs in mice demonstrate that RIG-I forms active signaling complexes without oligomerizing on RNA. These findings demonstrate that SLRs are potent therapeutic and investigative tools for targeted modulation of the innate immune system. RIG-I is an innate immune sensor that plays a key role in recognizing and responding to infection by RNA viruses (1, 2). RIG-I is activated in conditions that introduce a terminal, double-stranded RNA molecule into the cell. These molecules can include viral genomes, replication intermediates, and any other species containing a stable RNA duplex that is terminated with a 5'-triphosphate or diphosphate group (3,4). RIG-I activation by RNA leads to the induction of type I interferon (IFN) genes through the activation of its adaptor molecule, MAVS (5). Another member of the RIG-I-like receptors (RLRs), MDA5, binds to long stretches of double-stranded RNA and similarly triggers type I IFN production through MAVS (6). Type I IFNs induce hundreds of genes, collectively known as IFN-stimulated genes (ISGs), which have a variety of antiviral effector functions (7,8). Both the RNA duplex and 5'-triphosphate moieties are important for specific, high affinity binding and signaling by RIG-I (9-11), and through a series of recent crystal structures and functional studies of RNA recognition by the RIG-I receptor, the molecular basis for these effects has been elucidated (3,12).When appropriately delivered and modulated, RIG-I agonists would be promising tools for application in immuno-oncology (13-16), antiviral prophylaxis (17-20), and vaccine adjuvant development (21). However, all of these applications require a specific and potent RIG-I ligand that is functional in vivo. Previous work has suggested that RIG-I function can be controlled and exploited pharmacologically through stimulation with small, well-defined RNA ligands that are no larger than other therapeutically administered oligonucleotides (9,10,16). Structural studies, quantitative biochemical work, cell-based assays and imaging studies have all established that RIG-I is an "RNA end-capper" that encircles a 10-base-pair RNA duplex as a monomer and forms a network of specific interactions with the terminal base-pair and the 5'triphosphate (3,(10)(11)(12)(22)(23)(24)(25)(...

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Connexins and pannexins in the immune system and lymphatic organs

Cited by 44 publications

References 79 publications

Sustained Connexin43 Mimetic Peptide Release From Loaded Nanoparticles Reduces Retinal and Choroidal Photodamage

Sustained Connexin43 Mimetic Peptide Release From Loaded Nanoparticles Reduces Retinal and Choroidal Photodamage

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

A minimal RNA ligand for potent RIG-I activation in living mice

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