Antiadhesive Role of Apical Decay-accelerating Factor (CD55) in Human Neutrophil Transmigration across Mucosal Epithelia

Renal ischemia-reperfusion injury (IRI) is a feature of ischemic acute renal failure and it impacts both short- and long-term graft survival after kidney transplantation. Complement activation has been implicated in renal IRI, but its mechanism of action is uncertain and the determinants of complement activation during IRI remain poorly understood. We engineered mice deficient in two membrane complement regulatory proteins, CD55 and CD59, and used them to investigate the role of these endogenous complement inhibitors in renal IRI. CD55-deficient (CD55−/−), but not CD59-deficient (CD59−/−), mice exhibited increased renal IRI as indicated by significantly elevated blood urea nitrogen levels, histological scores, and neutrophil infiltration. Remarkably, although CD59 deficiency alone was inconsequential, CD55/CD59 double deficiency greatly exacerbated IRI. Severe IRI in CD55−/−CD59−/− mice was accompanied by endothelial deposition of C3 and the membrane attack complex (MAC) and medullary capillary thrombosis. Complement depletion in CD55−/−CD59−/− mice with cobra venom factor prevented these effects. Thus, CD55 and CD59 act synergistically to inhibit complement-mediated renal IRI, and abrogation of their function leads to MAC-induced microvascular injury and dysfunction that may exacerbate the initial ischemic assault. Our findings suggest a rationale for anti-complement therapies aimed at preventing microvascular injury during ischemia reperfusion, and the CD55−/−CD59−/− mouse provides a useful animal model in this regard.

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“…5C). The latter result may reflect a separate role of CD55 in regulating neutrophil migration as recently demonstrated by Lawrence et al (35).…”

Section: Discussionsupporting

confidence: 53%

Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59

Yamada

Miwa

Liu

et al. 2004

The Journal of Immunology

153

135

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“…The neutrophil can also represent the focus of analysis. For example, neutrophils employ several cell surface adhesion molecules to facilitate trans-epithelial migration 5,14,34,41,42 . Key cell-to-cell interactions can vary depending on the chemo-attractant driving migration and the tissue with which the neutrophils are interacting 34 .…”

Section: Representative Resultsmentioning

confidence: 99%

<em>In vitro</em> Coculture Assay to Assess Pathogen Induced Neutrophil Trans-epithelial Migration

Kusek

Pazos

Pirzai

et al. 2014

JoVE

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Mucosal surfaces serve as protective barriers against pathogenic organisms. Innate immune responses are activated upon sensing pathogen leading to the infiltration of tissues with migrating inflammatory cells, primarily neutrophils. This process has the potential to be destructive to tissues if excessive or held in an unresolved state. Cocultured in vitro models can be utilized to study the unique molecular mechanisms involved in pathogen induced neutrophil trans-epithelial migration. This type of model provides versatility in experimental design with opportunity for controlled manipulation of the pathogen, epithelial barrier, or neutrophil. Pathogenic infection of the apical surface of polarized epithelial monolayers grown on permeable transwell filters instigates physiologically relevant basolateral to apical trans-epithelial migration of neutrophils applied to the basolateral surface. The in vitro model described herein demonstrates the multiple steps necessary for demonstrating neutrophil migration across a polarized lung epithelial monolayer that has been infected with pathogenic P. aeruginosa (PAO1). Seeding and culturing of permeable transwells with human derived lung epithelial cells is described, along with isolation of neutrophils from whole human blood and culturing of PAO1 and nonpathogenic K12 E. coli (MC1000). The emigrational process and quantitative analysis of successfully migrated neutrophils that have been mobilized in response to pathogenic infection is shown with representative data, including positive and negative controls. This in vitro model system can be manipulated and applied to other mucosal surfaces. Inflammatory responses that involve excessive neutrophil infiltration can be destructive to host tissues and can occur in the absence of pathogenic infections. A better understanding of the molecular mechanisms that promote neutrophil trans-epithelial migration through experimental manipulation of the in vitro coculture assay system described herein has significant potential to identify novel therapeutic targets for a range of mucosal infectious as well as inflammatory diseases. Video LinkThe video component of this article can be found at

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“…However, the current literature suggests that other proteins and adhesion molecules on both PMN and epithelial cells play important roles in the regulation of PMN transepithelial migration at distinct points along the migration pathway. Such molecules include CD47, which serves to facilitate migration of PMN after initial adhesion, and CD55 (Lawrence et al, 2003), which is critical for PMN detachment at late stages of transmigration.…”

Section: Pmn Transepithelial Is a Multistep Event And Involves Jaml-cmentioning

confidence: 99%

“…Subsequently, PMN migrate between epithelial cells, where sequential CD11b/CD18-mediated binding to JAM-C at desmosomes is followed by JAML binding to CAR as PMN cross the TJ. Once at the apical surface of the epithelium, membrane proteins such as DAF (CD55; Lawrence et al, 2003) mediate PMN detachment. Studies aimed at identification of new adhesion molecules that regulate PMN transepithelial migration such as JAML and CAR may provide new targets for anti-inflammatory therapies.…”

Section: Pmn Transepithelial Is a Multistep Event And Involves Jaml-cmentioning

confidence: 99%

Neutrophil Migration across Tight Junctions Is Mediated by Adhesive Interactions between Epithelial Coxsackie and Adenovirus Receptor and a Junctional Adhesion Molecule-like Protein on Neutrophils

Zen

Liu

McCall

et al. 2005

MBoC

Self Cite

159

166

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Neutrophil (polymorphonuclear leukocytes [PMN]) transepithelial migration during inflammatory episodes involves INTRODUCTIONPolymorphonuclear leukocytes (PMN) are the first line of host defense against infection by bacterial pathogens and are rapidly recruited to sites of bacterial invasion. Because the majority of pathogens are encountered at mucosal surfaces, PMN must migrate out of the circulation, through the interstitium and across the epithelium to engage offending microbes. Although migration of PMN across the epithelium in this response is a terminal event, it is vitally important since elimination of pathogens and disease pathophysiology are direct consequences of PMN transepithelial migration. Despite the importance of this terminal event in the acute inflammatory response, many of the details regarding the regulation of PMN migration across mucosal surfaces remain undefined. Studies on this have revealed that migration of PMN across epithelial barriers involves a concerted series of cell-cell interactions between the PMN and epithelial cells (Zen and Parkos, 2003;Liu et al., 2004b). There is solid evidence that initial PMN-epithelial binding requires leukocyte ␤ 2 integrins, especially CD11b/CD18 (Parkos, 1997) and that the rate of PMN migration between epithelial cells is dependent on downstream signaling events from binding interactions between epithelial CD47 and PMNexpressed signal regulatory protein ␣ . Recent studies have begun to shed light on the nature of additional receptor-ligand pairs that may regulate PMN transepithelial migration in an organ-specific manner that are distinct from processes regulating transendothelial migration.Although the leukocyte ␤ 2 integrin CD11b/CD18 is a key adhesive element that regulates PMN transepithelial migration, there is evidence that additional adhesion molecules expressed on both PMN and epithelia must participate in PMN transepithelial migration, especially at the level of epithelial intercellular junctions. Recently, certain members of a growing family of proteins termed junctional adhesion molecules (JAMs) that are intercellular junction-associated, type-I Ig superfamily proteins (IgSFs) have been shown to serve as ligands for PMN and monocytes as they migrate across endothelial (Martin-Padura et al., 1998;Del Maschio et al., 1999;Johnson-Leger et al., 2002;Ostermann et al., 2002) and epithelial monolayers (Zen et al., 2004 (Ebnet et al., 2000;Takekuni et al., 2003) or desmosomes (Zen et al., 2004). JAMs are differentially expressed on a variety of endothelia, epithelia, and leukocytes and, under specific conditions, have been shown to mediate homophilic or heterophilic binding interactions that are important in regulating epithelial/endothelial monolayer barrier function and leukocyte transmigration (Martin-Padura et al., 1998;Cunningham et al., 2000;Liu et al., 2000;Cohen et al., 2001;Johnson-Leger et al., 2002;Liang et al., 2002;Mandell et al., 2004). In addition to homophilic/heterophilic interactions among JAM proteins, two family members, JAM-A ...

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Antiadhesive Role of Apical Decay-accelerating Factor (CD55) in Human Neutrophil Transmigration across Mucosal Epithelia

Cited by 72 publications

References 53 publications

Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59

Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59

<em>In vitro</em> Coculture Assay to Assess Pathogen Induced Neutrophil Trans-epithelial Migration

Neutrophil Migration across Tight Junctions Is Mediated by Adhesive Interactions between Epithelial Coxsackie and Adenovirus Receptor and a Junctional Adhesion Molecule-like Protein on Neutrophils

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