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David L Williams - One of the best experts on this subject based on the ideXlab platform.
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ScAvenger Receptor A cd204 A two edged sword in heAlth And diseAse
Critical Reviews in Immunology, 2014Co-Authors: Jim Kelley, Tammy R Ozment, John B Schweitzer, David L WilliamsAbstract:ScAvenger Receptor A (SR-A), Also known As the mAcrophAge ScAvenger Receptor And cluster of differentiAtion 204 (CD204), plAys roles in lipid metAbolism, Atherogenesis, And A number of metAbolic processes. However, recent evidence points to importAnt roles for SR-A in inflAmmAtion, innAte immunity, host defense, sepsis, And ischemic injury. Herein, we review the role of SR-A in inflAmmAtion, innAte immunity, host defense, sepsis, cArdiAc And cerebrAl ischemic injury, Alzheimer's diseAse, virus recognition And uptAke, bone metAbolism, And pulmonAry injury. Interestingly, SR-A is reported to be host protective in some diseAse stAtes, but there is Also compelling evidence thAt SR-A plAys A role in the pAthophysiology of other diseAses. These observAtions of both hArmful And beneficiAl effects of SR-A Are discussed here in the frAmework of inflAmmAtion, innAte immunity, And endoplAsmic reticulum stress.
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ScAvenger Receptor A sr A is required for lps induced tlr4 mediAted nf κb ActivAtion in mAcrophAges
Biochimica et Biophysica Acta, 2012Co-Authors: Li Liu, Jim Kelley, Xiaohui Wang, Ming Gao, Race L Kao, David L WilliamsAbstract:Recent evidence suggests thAt the mAcrophAge ScAvenger Receptor clAss A (SR-A, AkA, CD204) plAys A role in the induction of innAte immune And inflAmmAtory responses. We investigAted whether SR-A will cooperAte with Toll-like Receptors (TLRs) in response to TLR ligAnd stimulAtion. MAcrophAges (J774/A) were treAted with PAm2CSK4, (TLR2 ligAnd), Polyinosinic:polycytidylic Acid (Poly I:C) (TLR3 ligAnd), And LipopolysAcchArides (LPS) (TLR4 ligAnd) for 15 min in the presence or Absence of fucoidAn (the SR-A ligAnd). The levels of phosphorylAted IκBα (p-IκBα) were exAmined by Western blot. We observed thAt Poly I:C And LPS Alone, but not PAm2CSK4 or fucoidAn increAsed the levels of p-IκBα. However, LPS-induced increAses in p-IκBα levels were further enhAnced when presence of the fucoidAn. ImmunoprecipitAtion And double fluorescent stAining showed thAt LPS stimulAtion promotes SR-A AssociAtion with TLR4 in the presence of fucoidAn. To further confirm our observAtion, we isolAted peritoneAl mAcrophAges from SR-A deficient (SR-A(-/-)), TLR4(-/-) And wild type (WT) mice, respectively. The peritoneAl mAcrophAges were treAted with LPS for 15min in the presence And Absence of fucoidAn. We observed thAt LPS-stimulAted TNFα And IL-1β production wAs further enhAnced in the WT mAcrophAges, but did not in either TLR4(-/-) or SR-A(-/-) mAcrophAges, when fucoidAn wAs present. SimilArly, in the presence of fucoidAn, LPS-induced IκBα phosphorylAtion, NF-κB binding Activity, And AssociAtion between TLR4 And SR-A were significAntly enhAnced in WT mAcrophAges compAred with LPS stimulAtion Alone. The dAtA suggests thAt SR-A is needed for LPS-induced inflAmmAtory responses in mAcrophAges.
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ScAvenger Receptor clAss A hAs A centrAl role in cerebrAl ischemiA reperfusion injury
Journal of Cerebral Blood Flow and Metabolism, 2010Co-Authors: Fang Hua, Jim Kelley, John B Schweitzer, Li Liu, Race L Kao, John Kalbfleisch, David L WilliamsAbstract:The innAte immune response is involved in the pAthophysiology of cerebrAl ischemiA–reperfusion (I/R) injury. Recent evidence suggests thAt ScAvenger Receptors hAve A role in the induction of innAte immunity. In this study, we exAmined the role of ScAvenger Receptor A (SR-A) in focAl cerebrAl I/R injury. Both SR-A−/− mice (n=10) And Age-mAtched wild-type (WT) mice (n=9) were subjected to focAl cerebrAl ischemiA (60 minutes), followed by reperfusion (for 24 hours). InfArct size wAs determined by TTC (triphenyltetrAzolium chloride) stAining. The morphology of neurons in the brAin sections wAs exAmined by Nissl's stAining. ActivAtion of intrAcellulAr signAling wAs AnAlyzed by western blot. CerebrAl infArct size in SR-A−/− mice wAs significAntly reduced by 63.9% compAred with WT mice After cerebrAl I/R. In SR-A−/− mice, there wAs less neuronAl dAmAge in the hippocAmpus compAred with WT mice. Levels of FAsL, FAs, FADD, cAspAse-3 Activity, And terminAl deoynucleotidyl trAnsferAse-mediAted 2′-deoxyuridine 5′-triphosphAte-biotin nick end lAbeling-positive Apoptotic cells were significAntly increAsed in WT mice After cerebrAl I/R, but not in SR-A−/− mice. CerebrAl I/R increAsed nucleAr fActor-κB ActivAtion in WT mice, but not in SR-A−/− mice. These dAtA suggest thAt SR-A hAs A centrAl role in cerebrAl I/R injury And thAt suppression of SR-A mAy be A useful ApproAch for AmeliorAting brAin injury in stroke pAtients.
Vesa M. Olkkonen - One of the best experts on this subject based on the ideXlab platform.
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expression of humAn osbp relAted protein 1l in mAcrophAges enhAnces Atherosclerotic lesion development in ldl Receptor deficient mice
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Daoguang Yan, Matti Jauhiainen, Reeni B. Hildebrand, Christian Ehnholm, Miranda Van Eck, Theo J C Van Berkel, Ko Willems Van Dijk, Vesa M. OlkkonenAbstract:Objective— The purpose of this study wAs to Assess the role of mAcrophAge OSBP-relAted protein 1L (ORP1L) in the development of Atherosclerosis. Methods And Results— C57BL/6 mice overexpressing humAn ORP1L in mAcrophAges driven by ScAvenger Receptor A promoter were generAted. Bone mArrow (BM) of the mice wAs trAnsplAnted into LDLr−/− AnimAls, And Aortic root lesion AreA in the recipients wAs determined After Western-type diet feeding. The recipients of ORP1L BM displAyed 2.1-fold increAse (P<0.001) in lesion size As compAred with recipients of wild-type littermAte BM. MAcrophAges of the ORP1L BM recipients showed A decreAse in ABCG1 And APOE mRNAs And proteins, And An increAse in PLTP messAge; Also the plAsmA PLTP Activity wAs elevAted. The effect of ORP1L on cholesterol efflux wAs Assessed using mAcrophAges loAded with [3H]cholesterol oleAte-AcLDL or lAbeled with [3H]cholesterol. The ORP1L trAnsgenic mAcrophAges displAyed 30% reduction (P<0.01) in cholesterol efflux to HDL2, but not to ApoA-I. ORP1L wAs ...
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Expression of HumAn OSBP-RelAted Protein 1L in MAcrophAges EnhAnces Atherosclerotic Lesion Development in LDL Receptor–Deficient Mice
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Matti Jauhiainen, Reeni B. Hildebrand, Ko Willems Van Dijk, Theo J.c. Van Berkel, Christian Ehnholm, Vesa M. OlkkonenAbstract:Objective— The purpose of this study wAs to Assess the role of mAcrophAge OSBP-relAted protein 1L (ORP1L) in the development of Atherosclerosis. Methods And Results— C57BL/6 mice overexpressing humAn ORP1L in mAcrophAges driven by ScAvenger Receptor A promoter were generAted. Bone mArrow (BM) of the mice wAs trAnsplAnted into LDLr−/− AnimAls, And Aortic root lesion AreA in the recipients wAs determined After Western-type diet feeding. The recipients of ORP1L BM displAyed 2.1-fold increAse (P
Siamon Gordon - One of the best experts on this subject based on the ideXlab platform.
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mAcrophAge ScAvenger Receptor A promotes tumor progression in murine models of ovAriAn And pAncreAtic cAncer
Journal of Immunology, 2013Co-Authors: Claudine Neyen, Subhankar Mukhopadhyay, Annette Pluddemann, Siamon Gordon, Eleni Maniati, Maud Bossard, Thorsten HagemannAbstract:AlternAtively ActivAted mAcrophAges express the pAttern recognition Receptor ScAvenger Receptor A (SR-A). We demonstrAted previously thAt coculture of mAcrophAges with tumor cells upregulAtes mAcrophAge SR-A expression. We show in this study thAt mAcrophAge SR-A deficiency inhibits tumor cell migrAtion in A coculture AssAy. We further demonstrAte thAt coculture of tumor-AssociAted mAcrophAges And tumor cells induces secretion of fActors thAt Are recognized by SR-A on tumor-AssociAted mAcrophAges. We tentAtively identified severAl potentiAl ligAnds for the SR-A Receptor in tumor cell-mAcrophAge cocultures by mAss spectrometry. Competing with the coculture-induced ligAnd in our invAsion AssAy recApitulAtes SR-A deficiency And leAds to similAr inhibition of tumor cell invAsion. In line with our in vitro findings, tumor progression And metAstAsis Are inhibited in SR-A(-/-) mice in two in vivo models of ovAriAn And pAncreAtic cAncer. FinAlly, treAtment of tumor-beAring mice with 4F, A smAll peptide SR-A ligAnd Able to compete with physiologicAl SR-A ligAnds in vitro, recApitulAtes the inhibition of tumor progression And metAstAsis observed in SR-A(-/-) mice. Our observAtions suggest thAt SR-A mAy be A potentiAl drug tArget in the prevention of metAstAtic cAncer progression.
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IdentificAtion of ScAvenger Receptor LigAnds
Methods in molecular biology (Clifton N.J.), 2011Co-Authors: Claudine Neyen, Annette Pluddemann, Siamon GordonAbstract:ScAvenger Receptors (SRs) Are structurAlly diverse but functionAlly relAted innAte immune Receptors involved in defence And cleArAnce mechAnisms. Their broAd specificity relies on evolutionArily conserved pAttern recognition domAins which interAct with A vAriety of microbiAl, Apoptotic And modified self ligAnds. Studies of immune functions of SR-expressing cells require the identificAtion of interAction pArtners for SRs. We hAve developed An ELISA-bAsed method which Allows for lArge-scAle high-throughput screening of complex mixtures. The AssAy successfully identified bActeriAl And plAsmA ligAnds for mAcrophAge ScAvenger Receptor A And cAn be AdApted to screen for novel exogenous or endogenous ligAnds for Any immune Receptor of interest.
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sr A mArco mediAted ligAnd delivery enhAnces intrAcellulAr tlr And nlr function but ligAnd scAvenging from cell surfAce limits tlr4 response to pAthogens
Blood, 2011Co-Authors: Subhankar Mukhopadhyay, Audrey Varin, Yunying Chen, Baoying Liu, Karl Tryggvason, Siamon GordonAbstract:PhAgocytic And pAthogen sensing Receptors Are responsible for pArticle uptAke And inflAmmAtion. It is uncleAr how these Receptors' systems influence eAch other's function to shApe An innAte response. The clAss-A ScAvenger Receptors SR-A (ScAvenger Receptor A) And MARCO (mAcrophAge Receptor with collAgenous structure) Are 2 well-chArActerized phAgocytic Receptors thAt Are unAble to initiAte inflAmmAtory responses by themselves, yet Are implicAted in the pAthogenesis of vArious inflAmmAtory disorders. However, the mechAnism for such An AppArent discrepAncy is still uncleAr. We utilized SR-A(-/-), MARCO(-/-), And SR-A(-/-)-MARCO(-/-) mice, Along with microbe-derived, environmentAl, And synthetic polyAnions to Assess the inflAmmAtory responses following combinAtoriAl ligAtion of SR-A/MARCO And selected Toll-like Receptors (TLRs) And nucleotide-binding oligomerizAtion domAin (NOD)-like Receptors (NLRs) by their shAred ligAnds. In Addition to ligAting SR-A And MARCO, these Agonists Also selectively ActivAted the cell-surfAce sensor TLR4, endosomAl TLR3, And the cytosolic NOD2 And NALP3 (NACHT domAin-, leucine-rich repeAt-, And pyrin domAin-contAining protein 3). We show thAt, following recognition of common ligAnds, SR-A And MARCO AttenuAte TLR4-mediAted responses while enhAncing responses by the intrAcellulAr TLR3, NOD2, And NALP3. We conclude thAt SR-A/MARCO-mediAted rApid ligAnd internAlizAtion prevented sensing by surfAce TLRs while increAsing ligAnd AvAilAbility in intrAcellulAr compArtments, thus Allowing sensing And robust responses by intrAcellulAr sensors.
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AlternAtive ActivAtion of mAcrophAges by IL-4 impAirs phAgocytosis of pAthogens but potentiAtes microbiAl-induced signAlling And cytokine secretion.
Blood, 2010Co-Authors: Audrey Varin, Subhankar Mukhopadhyay, Georges Herbein, Siamon GordonAbstract:AlternAtively ActivAted mAcrophAges plAy An importAnt role in host defense in the context of A T helper type 2 (Th2) microenvironment such As pArAsitic infection. However, the role of these mAcrophAges during secondAry chAllenge with Th1 pAthogens is poorly defined. In this study, thioglycollAte-elicited mouse peritoneAl mAcrophAges were treAted with interleukin-4 (IL-4) or IL-13 in vitro And chAllenged with NeisseriA meningitidis. After 8 to 12 hours of IL-4 pretreAtment, the nonopsonic phAgocytic uptAke of N meningitidis wAs mArkedly reduced, depending on the common IL-4RAlphA chAin, but independent of ScAvenger Receptor A And mAcrophAge Receptor with collAgenous structure (MARCO), 2 known Receptors for N meningitidis. Inhibition of phAgocytosis extended to severAl other microbiAl pArticles, zymosAn, And other bActeriA. ConcomitAntly, IL-4 potentiAted the secretion of proinflAmmAtory cytokines, After AdditionAl bActeriAl stimulAtion, which depended on the MyD88 signAling pAthwAy. SimilAr results were obtAined After intrAperitoneAl stimulAtion of IL-4 And N meningitidis in vivo. Further in vitro studies showed A striking correlAtion with inhibition of Akt phosphorylAtion And stimulAtion of the mitogen-ActivAted protein kinAse pAthwAy; inhibition of phAgocytosis wAs AssociAted with inhibition of phAgosome formAtion. These findings Are relevAnt to host defense in mixed infections within A Th2 microenvironment And shed light on immunologic functions AssociAted with AlternAtive priming And full ActivAtion of mAcrophAges.
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the mAcrophAge ScAvenger Receptor A is host protective in experimentAl meningococcAl septicAemiA
PLOS Pathogens, 2009Co-Authors: Annette Pluddemann, Katherine Makepeace, Richard E Moxon, Siamon GordonAbstract:MAcrophAge ScAvenger Receptor A (SR-A) is A mAjor non-opsonic Receptor for NeisseriA meningitidis on mononucleAr phAgocytes in vitro, And the surfAce proteins NMB0278, NMB0667, And NMB1220 hAve been identified As ligAnds for SR-A. In this study we AscertAin the in vivo role of SR-A in the recognition of N. meningitidis MC58 (serogroup B) in A murine model of meningococcAl septicAemiA. We infected wild-type And SR-A−/− AnimAls intrAperitoneAlly with N. meningitidis MC58 And monitored their heAlth over A period of 50 hours. We Also determined the levels of bActerAemiA in the blood And spleen, And meAsured levels of the pro-inflAmmAtory cytokine interleukin-6 (IL-6). The heAlth of SR-A−/− AnimAls deteriorAted more rApidly, And they showed A 33% reduction in survivAl compAred to wild-type AnimAls. SR-A−/− AnimAls consistently exhibited higher levels of bActerAemiA And increAsed levels of IL-6, compAred to wild-type AnimAls. Subsequently, we constructed A bActeriAl mutAnt (MC58-278-1220) lAcking two of the SR-A ligAnds, NMB0278 And NMB1220. MutAtion of NMB0667 proved to be lethAl. When mice were infected with the mutAnt bActeriA MC58-278-1220, no significAnt differences could be observed in the heAlth, survivAl, bActerAemiA, And cytokine production between wild-type And SR-A−/− AnimAls. OverAll, mutAnt bActeriA AppeAred to cAuse less severe symptoms of septicAemiA, And A competitive index AssAy showed thAt higher levels of wild-type bActeriA were recovered when AnimAls were infected with A 1∶1 rAtio of wild-type MC58 And mutAnt MC58-278-1220 bActeriA. These dAtA represent the first report of the protective role of SR-A, A mAcrophAge-restricted, non-opsonic Receptor, in meningococcAl septicAemiA in vivo, And the importAnce of the recognition of bActeriAl protein ligAnds, rAther thAn lipopolysAcchAride.
Tatsuhiko Kodama - One of the best experts on this subject based on the ideXlab platform.
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mAnnose binding lectin Augments the uptAke of lipid A stAphylococcus Aureus And escherichiA coli by kupffer cells through increAsed cell surfAce expression of ScAvenger Receptor A
Journal of Immunology, 2006Co-Authors: Kei Ono, Chiaki Nishitani, Hiroaki Mitsuzawa, Hitomi Sano, Hiroshi Suzuki, Tatsuhiko Kodama, Takeyuki Shimizu, Nobuhiro Fujii, Koichi Fukase, Koichi HirataAbstract:We investigAted roles of ScAvenger Receptor A (SR-A) And mAnnose-binding lectin (MBL) in the uptAke of endotoxin And bActeriA by Kupffer cells. When [ 3 H]lipid A wAs injected into retro-orbitAl plexus of mice, significAntly less AccumulAtion of lipid A in the liver wAs observed in SR-A-deficient mice And wild-type mice coinjected with fucoidAn or AcetylAted low-density lipoprotein, which Are known ligAnds for SR-A. IsolAted Kupffer cells were Able to tAke up [ 3 H]lipid A in A time-dependent mAnner. The Amount of lipid A AssociAted with nonAdherent Kupffer cells derived from SR-A-deficient mice wAs reduced by ∼80% when compAred with wild-type cells, indicAting An importAnt role of SR-A in endotoxin uptAke by Kupffer cells. The lipid A uptAke by Kupffer cells wAs significAntly enhAnced in the presence of rMBL. CoincubAtion of fucoidAn with [ 3 H]lipid A significAntly inhibited the bAsAl And the MBL-stimulAted uptAke of lipid A by Kupffer cells. PreincubAtion of MBL with Kupffer cells Also increAsed the uptAke of lipid A. These results indicAte thAt MBL Augments the SR-A-mediAted uptAke of lipid A by Kupffer cells. Consistently, the exposure of MBL to Kupffer cells increAsed cell surfAce SR-A expression. The phAgocytosis of StAphylococcus Aureus And EscherichiA coli by Kupffer cells wAs Also enhAnced by preincubAtion of MBL with the cells. In Addition, MBL bound to lipid A, LPS, And S. Aureus , And precipitAted S. Aureus . This study demonstrAtes importAnt roles of SR-A And MBL in the uptAke of endotoxin And bActeriA by Kupffer cells.
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defective microArchitecture of the spleen mArginAl zone And impAired response to A thymus independent type 2 Antigen in mice lAcking ScAvenger Receptors mArco And sr A
Journal of Immunology, 2005Co-Authors: Yunying Chen, Tatsuhiko Kodama, Timo Pikkarainen, Georg Kraal, Outi Elomaa, Raija Soininen, Karl TryggvasonAbstract:The mAcrophAge ScAvenger Receptor mAcrophAge Receptor with A collAgenous structure (MARCO) is expressed in mice by the mArginAl zone mAcrophAges of the spleen And by mAcrophAges of the medullAry cords of lymph nodes, As well As the peritoneAl mAcrophAges. MARCO is A relAtive of ScAvenger Receptor A (SR-A), the more widely expressed prototypic member of the ScAvenger Receptor fAmily. In the present study, we found thAt genetic AblAtion of MARCO leAds to chAnges in the orgAnizAtion of the splenic mArginAl zone, And cAuses A significAnt reduction in the size of the resident peritoneAl mAcrophAge populAtion, possibly due to chAnges in Adhesion And migrAtion cApAcity. In mice lAcking both MARCO And SR-A these effects Are even more AppArent. During ontogeny, the AppeArAnce And orgAnizAtion of the MARCO-expressing cells in the spleen precedes the AppeArAnce of other Receptors on mAcrophAges in the mArginAl zone, such As SIGNR1 And Siglec-1. In the Absence of MARCO, A cleAr delAy in the orgAnizAtion of the mArginAl zone wAs observed. SimilAr findings were seen when the reAppeArAnce of the vArious subsets from precursors wAs studied After depleting mAcrophAges from the Adult spleen by A liposome treAtment. When chAllenged with A pneumococcAl polysAcchAride vAccine, A T-independent type 2 Ag for which An intAct mArginAl zone is cruciAl, the knockout mice exhibited A cleArly impAired response. These findings suggest thAt both MARCO And SR-A, in Addition to being importAnt ScAvenger Receptors, could be involved in the positioning And differentiAtion of mAcrophAges, possibly through interAction with endogenous ligAnds.
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pulmonAry surfActAnt protein A Augments the phAgocytosis of streptococcus pneumoniAe by AlveolAr mAcrophAges through A cAsein kinAse 2 dependent increAse of cell surfAce locAlizAtion of ScAvenger Receptor A
Journal of Biological Chemistry, 2004Co-Authors: Koji Kuronuma, Kazumi Kudo, Hitomi Sano, Hiroshi Suzuki, Nobuhiro Fujii, Kazunori Kato, Naoki Hyakushima, Shinichi Yokota, Hiroki Takahashi, Tatsuhiko KodamaAbstract:AbstrAct PulmonAry surfActAnt proteins A (SP-A) And D (SP-D), members of the collectin fAmily, plAy importAnt roles in the innAte immune system of the lung. Here, we show thAt SP-A but not SP-D Augmented phAgocytosis of Streptococcus pneumoniAe by AlveolAr mAcrophAges, independent of its binding to the bActeriA. AnAlysis of the SP-A/SP-D chimerAs, in which progressively longer cArboxyl-terminAl regions of SP-A were replAced with the corresponding SP-D regions, hAs reveAled thAt the SP-D region Gly346-Phe355 cAn be substituted for the SP-A region Leu219-Phe228 without Altering the SP-A Activity of enhAncing the phAgocytosis And thAt the SP-A region Cys204-Cys218 is required for the SP-A-mediAted phAgocytosis. AcetylAted low density lipoprotein significAntly reduced the SP-A-stimulAted uptAke of the bActeriA. SP-A fAiled to enhAnce the phAgocytosis of S. pneumoniAe by AlveolAr mAcrophAges derived from ScAvenger Receptor A (SR-A)-deficient mice, demonstrAting thAt SP-A Augments SRA-mediAted phAgocytosis. PreincubAtion of mAcrophAges with SP-A At 37 °C but not At 4 °C stimulAted the phAgocytosis. The SP-A-mediAted enhAnced phAgocytosis wAs not inhibited by the presence of cycloheximide. SP-A increAsed cell surfAce locAlizAtion of SR-A thAt wAs inhibitAble by Apigenin, A cAsein kinAse 2 (CK2) inhibitor. SP-A-treAted mAcrophAges exhibited significAntly greAter binding of AcetylAted low density lipoprotein thAn nontreAted cells. The SP-A-stimulAted phAgocytosis wAs Also Abolished by Apigenin. In Addition, SP-A stimulAted CK2 Activity. These results demonstrAte thAt SP-A enhAnces the phAgocytosis of S. pneumoniAe by AlveolAr mAcrophAges through A CK2-dependent increAse of cell surfAce SR-A locAlizAtion. This study reveAls A novel mechAnism of bActeriAl cleArAnce by AlveolAr mAcrophAges.
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phosphAtidylinositol 3 oh kinAse Akt protein kinAse b pAthwAy mediAtes gAs6 induction of ScAvenger Receptor A in immortAlized humAn vAsculAr smooth muscle cell line
Arteriosclerosis Thrombosis and Vascular Biology, 2001Co-Authors: Wen Ming Cao, Tatsuhiko Kodama, Koji Murao, Hitomi Imachi, Makoto Sato, Toru Nakano, Yasuyuki Sasaguri, Norman C W Wong, Jiro Takahara, Toshihiko IshidaAbstract:The growth Arrest-specific gene 6 encodes A secreted protein, GAs6, which wAs originAlly identified As the ligAnd of A Receptor, Axl, with tyrosine kinAse Activity. The clAss A ScAvenger Receptor (SRA) mediAtes lipid uptAke into cells, leAding to the formAtion of foAm cells, An importAnt step in Atherogenesis. Although GAs6 induces SRA expression, the underlying mechAnism is not cleAr. In this report, we show thAt the GAs6-induced expression of SRA wAs mediAted by the phosphAtidylinositol 3-OH kinAse (PI3-kinAse)-serine/threonine kinAse (Akt/protein kinAse B [PKB]) pAthwAy involving Akt phosphorylAtion. This pAthwAy wAs ActivAted by exposure to GAs6. Furthermore, the effect of GAs6 wAs AbrogAted by wortmAnnin, A specific inhibitor of PI3-kinAse. We Also demonstrAted thAt the constitutively Active form of Akt enhAnced Activity of the SRA promoter but thAt the dominAnt-negAtive mutAnt of Akt completely Abolished the expression of SRA After treAtment with GAs6. These results show thAt the PI3-kinAse-Akt/PKB pAthwAy pArticipAtes in GAs6-induced SRA expression And suggests thAt the ActivAtion of Akt/PKB plAys An importAnt role in GAs6-induced Atherosclerosis And foAm cell formAtion in humAn vAsculAr smooth muscle cells.
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reduced Atherosclerotic lesions in mice deficient for totAl or mAcrophAge specific expression of ScAvenger Receptor A
Arteriosclerosis Thrombosis and Vascular Biology, 2000Co-Authors: Vladimir R Babaev, Linda A Gleaves, Kathy J Carter, Hiroshi Suzuki, Tatsuhiko Kodama, Sergio Fazio, Macrae F LintonAbstract:AbstrAct —The Absence of the ScAvenger Receptor A (SR-A)-I/II hAs produced vAriAble effects on Atherosclerosis in different murine models. Therefore, we exAmined whether SR-AI/II deficiency Affected Atherogenesis in C57BL/6 mice, An inbred strAin known to be susceptible to diet-induced Atherosclerotic lesion formAtion, And whether the deletion of mAcrophAge SR-AI/II expression would modulAte lesion growth in C57BL/6 mice And LDL Receptor (LDLR) −/− mice. SR-AI/II–deficient (SR-AI/II −/− ) femAle And mAle mice on the C57BL/6 bAckground were chAllenged with A butterfAt diet for 30 weeks. No differences were detected in plAsmA lipids between SR-AI/II −/− And SR-AI/II +/+ mice, whereAs both femAle And mAle SR-AI/II −/− mice hAd A tremendous reduction (81% to 86%) in lesion AreA of the proximAl AortA compAred with SR-AI/II +/+ mice. Next, to AnAlyze the effect of mAcrophAge-specific SR-AI/II deficiency in Atherogenesis, femAle C57BL/6 mice were lethAlly irrAdiAted, trAnsplAnted with SR-AI/II −/− or SR-AI/II +/+ fetAl liver cells, And chAllenged with the butterfAt diet for 16 weeks. In A sepArAte experiment, mAle LDLR −/− mice were reconstituted with SR-AI/II −/− or SR-AI/II +/+ fetAl liver cells And chAllenged with A Western diet for 10 weeks. No significAnt differences in plAsmA lipids And lipoprotein profiles were noted between the control And experimentAl groups in either experiment. SR-AI/II −/− →C57BL/6 mice, however, hAd A 60% reduction in lesion AreA of the proximAl AortA compAred with SR-AI/II +/+ →C57BL/6 mice. A similAr level of reduction (60%) in lesion AreA wAs noted in the proximAl AortA And the entire AortA en fAce of SR-AI/II −/− →LDLR −/− mice compAred with SR-AI/II +/+ →LDLR −/− mice. These results demonstrAte in vivo thAt SR-AI/II expression hAs no impAct on plAsmA lipid levels And thAt mAcrophAge SR-AI/II contributes significAntly to Atherosclerotic lesion formAtion.
Xiangyang Wang - One of the best experts on this subject based on the ideXlab platform.
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ScAvenger Receptor A restrAins t cell ActivAtion And protects AgAinst concAnAvAlin A induced hepAtic injury
Hepatology, 2013Co-Authors: Daming Zuo, Chunqing Guo, Hongxia Wang, Jie Qian, John R Subjeck, Huiping Zhou, Arun J Sanyal, Zhengliang Chen, Xiangyang WangAbstract:NegAtive feedbAck immune mechAnisms Are essentiAl for mAintenAnce of hepAtic homeostAsis And prevention of immune-mediAted liver injury. We show here thAt ScAvenger Receptor A (SRA/CD204), A pAttern recognition molecule, is highly up-regulAted in the livers of pAtients with Autoimmune or virAl hepAtitis, And of mice during concAnAvAlin A (Con A)-induced hepAtitis (CIH). Strikingly, genetic SRA AblAtion strongly sensitizes mice to Con A-induced liver injury. SRA loss, increAsed mortAlity And liver pAthology correlAte with excessive production of IFN-γ And heightened ActivAtion of T cells. IncreAsed liver expression of SRA primArily occurs in mobilized hepAtic myeloid cells during CIH, including CD11b+Gr-1+ cells. MechAnistic studies estAblish thAt SRA on these cells functions As A negAtive regulAtor limiting T-cell Activity And cytokine production. SRA-mediAted protection from CIH is further vAlidAted by Adoptive trAnsfer of SRA+ hepAtic mononucleAr cells or AdministrAtion of A lentivirus-expressing SRA, which effectively AmeliorAtes Con A-induced hepAtic injury. Also, CIH And clinicAl hepAtitis Are AssociAted with increAsed levels of soluble SRA. This soluble SRA displAys A direct T-cell inhibitory effect And is cApAble of mitigAting Con A-induced liver pAthology. Conclusion: Our findings demonstrAte An unexpected role of SRA in AttenuAtion of Con A-induced, T-cell-mediAted hepAtic injury. We propose thAt SRA serves As An importAnt negAtive feedbAck mechAnism in liver immune homeostAsis, And mAy be exploited for therApeutic treAtment of inflAmmAtory liver diseAses. (HEPATOLOGY 2013)
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pAttern recognition ScAvenger Receptor cd204 AttenuAtes toll like Receptor 4 induced nf κb ActivAtion by directly inhibiting ubiquitinAtion of tumor necrosis fActor tnf Receptor AssociAted fActor 6
Journal of Biological Chemistry, 2011Co-Authors: Chunqing Guo, Daming Zuo, John R Subjeck, Yanping Wang, Hyung L Kim, Xiangyang WangAbstract:The collAborAtion And cross-tAlk between different clAsses of innAte pAttern recognition Receptors Are cruciAl for A well coordinAted inflAmmAtory response And host defense. Here we report A previously unrecognized role of ScAvenger Receptor A (SRA; Also known As CD204) As A signAling regulAtor in the context of Toll-like Receptor 4 (TLR4) ActivAtion. We show thAt SRA/CD204 deficiency leAds to greAter sensitivity to LPS-induced endotoxic shock. SRA/CD204 down-regulAtes inflAmmAtory gene expression in dendritic cells by suppressing TLR4-induced ActivAtion of the trAnscription fActor NF-κB. For the first time, we demonstrAte thAt SRA/CD204 executes its regulAtory functions by directly interActing with the TRAF-C domAin of TNF Receptor-AssociAted fActor 6 (TRAF6), resulting in inhibition of TRAF6 dimerizAtion And ubiquitinAtion. The AttenuAtion of NF-κB Activity by SRA/CD204 is independent of its ligAnd-binding domAin, indicAting thAt the signAling-regulAtory feAture of SRA/CD204 cAn be uncoupled from its conventionAl endocytic functions. Collectively, we hAve identified the moleculAr linkAge between SRA/CD204 And the TLR4 signAling pAthwAys, And our results reveAl A novel mechAnism by which A non-TLR pAttern recognition Receptor restricts TLR4 ActivAtion And consequent inflAmmAtory response.
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Hsp110 And Grp170, members of the Hsp70 superfAmily, bind to ScAvenger Receptor-A And ScAvenger Receptor expressed by endotheliAl cells-I.
European journal of immunology, 2007Co-Authors: John G. Facciponte, Xiangyang Wang, John R SubjeckAbstract:HeAt shock protein 110 (hsp110) And glucose-regulAted protein (grp170) Act As Anti-cAncer vAccines when complexed to tumor Antigens by heAt shock. It hAs been proposed thAt Receptors on Antigen-presenting cells contribute to HSP-mediAted immune responses. Here, we show thAt hsp110 binds in A Receptor-mediAted mAnner to RAW264.7 mAcrophAges, As does grp170. This hsp110/grp170 binding is inhibited by ScAvenger Receptor ligAnds, suggesting A role for ScAvenger Receptors As binding structures. We exAmined ScAvenger Receptor clAss A (SR-A) And ScAvenger Receptor expressed by endotheliAl cells-I (SREC-I). We show thAt hsp110/grp170 binds to both SR-A- And SREC-I-expressing CHO cells in A sAturAble mAnner And ScAvenger Receptor ligAnds inhibit binding. Hsp110 Also sAturAbly binds mouse bone mArrow-derived dendritic cells (bmDC) And is inhibited by ScAvenger Receptor ligAnds. When An hsp110-rAt neu (intrAcellulAr domAin) heAt shock complex vAccine is used to pulse mouse bmDC in vitro, An induction of IFN-γ secretion is observed by CD8+ T lymphocytes isolAted from vAccine-immunized mice. This immune response is inhibited by the ApplicAtion of ScAvenger Receptor ligAnds to bmDC. Thus, SR-A And SREC-I AppeAr to contribute to the binding of hsp110 And grp170 on APC. ScAvenger Receptors, in generAl, contribute to the cross-presentAtion of hsp110-chAperoned protein Antigen.
