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1.  The complement anaphylatoxin C5a receptor contributes to obese adipose tissue inflammation and insulin resistance1 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(8):10.4049/jimmunol.1300038.
Obese adipose tissue (AT)3 inflammation contributes critically to development of insulin resistance. The complement anaphylatoxin C5a receptor (C5aR) has been implicated in inflammatory processes and as regulator of macrophage activation and polarization. However, the role of C5aR in obesity and AT inflammation has not been addressed. We engaged the model of diet-induced obesity and found that expression of C5aR was significantly upregulated in the obese AT, as compared to lean AT. Additionally, C5a was present in obese AT in the proximity of macrophage-rich crown-like structures. C5aR-sufficient and –deficient mice were fed a high fat diet (HFD) or a normal diet (ND). C5aR-deficiency was associated with increased AT weight upon ND in males but not in females and with increased adipocyte size upon ND and HFD conditions in males. However, obese C5aR−/− mice displayed improved systemic and AT insulin sensitivity. Improved AT insulin sensitivity in C5aR−/− mice was associated with reduced accumulation of total and pro-inflammatory M1 macrophages in the obese AT, increased expression of IL-10 and decreased AT fibrosis. In contrast no difference in beta cell mass was observed due to C5aR-deficiency under HFD. These results suggest that C5aR contributes to macrophage accumulation and M1 polarization in the obese AT and thereby to AT dysfunction and development of AT insulin resistance.
PMCID: PMC3817864  PMID: 24043887
obesity; inflammation; insulin resistance; diabetes; complement
2.  Expression, Localization, and Function of Junctional Adhesion Molecule-C (JAM-C) in Human Retinal Pigment Epithelium 
To determine the localization of JAM-C in human RPE and characterize its functions.
Immunofluorescence, Western blot, and PCR was used to identify the localization and expression of JAM-C, ZO-1, N-cadherin, and ezrin in cultures of human fetal RPE (hfRPE) with or without si-RNA mediated JAM-C knockdown and in adult native RPE wholemounts. A transepithelial migration assay was used to study the migration of leukocytes through the hfRPE monolayer.
JAM-C localized at the tight junctions of cultured hfRPE cells and adult native RPE. During initial junction formation JAM-C was recruited to the primordial cell– cell contacts and after JAM-C knockdown, the organization of N-cadherin and ZO-1 at those contacts was disrupted. JAM-C knockdown caused a delay in the hfRPE cell polarization, as shown by reduced apical staining of ezrin. JAM-C inhibition significantly decreased the chemokine-induced transmigration of granulocytes but not monocytes through the hfRPE monolayer.
JAM-C localizes specifically in the tight junctions of hfRPE and adult native RPE. It is important for tight junction formation in hfRPE, possibly by regulating the recruitment of N-cadherin and ZO-1 at the cell– cell contacts, and has a role in the polarization of hfRPE cells. Finally, JAM-C promotes the basal-to-apical transmigration of granulocytes but not monocytes through the hfRPE monolayer.
PMCID: PMC2752302  PMID: 19060272
4.  Del-1 is an endogenous inhibitor of leukocyte-endothelial adhesion limiting inflammatory cell recruitment& 
Science (New York, N.Y.)  2008;322(5904):1101-1104.
Leukocyte recruitment to sites of infection or inflammation requires multiple adhesive events. While numerous players promoting leukocyte-endothelial interactions have been characterized, functionally important endogenous inhibitors of leukocyte adhesion have not been identified. Here, we describe the endothelial-derived secreted molecule, developmental endothelial locus-1 (Del-1), as an anti-adhesive factor that interferes with the integrin LFA-1-dependent leukocyte-endothelial adhesion. Endothelial Del-1-deficiency increased LFA-1-dependent leukocyte adhesion in vitro and in vivo. Del-1-/-mice displayed significantly higher neutrophil accumulation in LPS-induced lung inflammation in vivo, which was reversed in Del-1/LFA-1-double deficient mice. Thus, Del-1 is an endogenous inhibitor of inflammatory cell recruitment and could provide a basis for targeting leukocyte-endothelial interactions in disease.
PMCID: PMC2753175  PMID: 19008446
5.  Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin–mediated cell–cell contacts 
The Journal of Experimental Medicine  2006;203(12):2703-2714.
We recently reported that junctional adhesion molecule (JAM)-C plays a role in leukocyte transendothelial migration. Here, the role of JAM-C in vascular permeability was investigated in vitro and in vivo. As opposed to macrovascular endothelial cells that constitutively expressed JAM-C in cell–cell contacts, in quiescent microvascular endothelial cells, JAM-C localized mainly intracellularly, and was recruited to junctions upon short-term stimulation with vascular endothelial growth factor (VEGF) or histamine. Strikingly, disruption of JAM-C function decreased basal permeability and prevented the VEGF- and histamine-induced increases in human dermal microvascular endothelial cell permeability in vitro and skin permeability in mice. Permeability increases are essential in angiogenesis, and JAM-C blockade reduced hyperpermeability and neovascularization in hypoxia-induced retinal angiogenesis in mice. The underlying mechanisms of the JAM-C–mediated increase in endothelial permeability were studied. JAM-C was essential for the regulation of endothelial actomyosin, as revealed by decreased F-actin, reduced myosin light chain phosphorylation, and actin stress fiber formation due to JAM-C knockdown. Moreover, the loss of JAM-C expression resulted in stabilization of VE-cadherin–mediated interendothelial adhesion in a manner dependent on the small GTPase Rap1. Together, through modulation of endothelial contractility and VE-cadherin–mediated adhesion, JAM-C helps to regulate vascular permeability and pathologic angiogenesis.
PMCID: PMC2118160  PMID: 17116731

Results 1-5 (5)