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Jennifer L Auger, Stefanie Haasken, Bryce A Binstadt
INTRODUCTION: The effector functions of immunoglobulin G (IgG) are mediated by interaction of its Fc region with Fc receptors (FcγRs) and/or the complement system. The three main pathways of complement activation converge at C3. However, C3-independent pathways can activate C5 and other downstream complement components during IgG-initiated inflammatory responses. These C3-independent pathways of C5 activation are triggered by activating FcγRs in some systems or can be activated by factors of the coagulation cascade such as thrombin...
December 13, 2012: Arthritis Research & Therapy
Tania N Crotti, Anak A S S K Dharmapatni, Ekram Alias, Andrew C W Zannettino, Malcolm D Smith, David R Haynes
INTRODUCTION: The immunoreceptor tyrosine-based activation motif (ITAM) pathway provides osteoclast co-stimulatory signals and regulates proliferation, survival and differentiation of effector immune cells. In the osteoclast, the receptors Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Osteoclast Associated Receptor (OSCAR) and their respective adaptor proteins, DAP12 and FcRγ mediate ITAM signals and induce calcium signaling and the crucial transcription factor, NFATc1...
2012: Arthritis Research & Therapy
Wei Zou, Tingting Zhu, Clarissa S Craft, Thomas J Broekelmann, Robert P Mecham, Steven L Teitelbaum
Despite evidence that DAP12 regulates osteoclasts, mice lacking the ITAM-bearing protein exhibit only mild osteopetrosis. Alternatively, Dap12(-/-) mice, also lacking FcRgamma, are severely osteopetrotic, suggesting that FcRgamma compensates for DAP12 deficiency in the bone-resorbing polykaryons. Controversy exists, however, as to whether these co-stimulatory molecules regulate differentiation of osteoclasts or the capacity of the mature cell to degrade bone. We find that Dap12(-/-) osteoclasts differentiate normally when generated on osteoblasts but have a dysfunctional cytoskeleton, impairing their ability to transmigrate through the osteoblast layer and resorb bone...
September 1, 2010: Journal of Cell Science
Tatsuya Kawaguchi, Ryuji Hashimoto, Hiroshi Yokota
We have demonstrated that a unique megakaryocytic cell line UT-7/TPO could respond to one of the primary platelet signals through GP (glycoprotein) VI and a secondary signal of the AA (arachidonic acid) cascade. Unlike other megakaryocytic cell lines, UT-7/TPO was found to express GPVI and its associate signal molecule of FcRgamma (Fc receptor gamma chain). When UT-7/TPO was stimulated with the GPVI agonist convulxin, the [Ca2+]i (intracellular Ca2+) was elevated in a convulxin concentration-dependent manner, and [Ca2+]i elevation was blocked by pretreatment with the Src family kinase inhibitor PP2 and the phospholipase inhibitor U73122...
September 2010: Cell Biology International
Shinobu Saijo, Satoshi Ikeda, Keiko Yamabe, Shigeru Kakuta, Harumichi Ishigame, Aoi Akitsu, Noriyuki Fujikado, Toshimasa Kusaka, Sachiko Kubo, Soo-hyun Chung, Ryohei Komatsu, Noriko Miura, Yoshiyuki Adachi, Naohito Ohno, Kazutoshi Shibuya, Natsuo Yamamoto, Kazuyoshi Kawakami, Sho Yamasaki, Takashi Saito, Shizuo Akira, Yoichiro Iwakura
Dectin-2 (gene symbol Clec4n) is a C-type lectin expressed by dendritic cells (DCs) and macrophages. However, its functional roles and signaling mechanisms remain to be elucidated. Here, we generated Clec4n(-/-) mice and showed that this molecule is important for host defense against Candida albicans (C. albicans). Clec4n(-/-) DCs had virtually no fungal alpha-mannan-induced cytokine production. Dectin-2 signaling induced cytokines through an FcRgamma chain and Syk-CARD9-NF-kappaB-dependent signaling pathway without involvement of MAP kinases...
May 28, 2010: Immunity
Alexandra Mazharian, Steve G Thomas, Tarvinder S Dhanjal, Christopher D Buckley, Steve P Watson
Migration of megakaryocytes (MKs) from the proliferative osteoblastic niche to the capillary-rich vascular niche is essential for proplatelet formation and platelet release. In this study, we explore the role of surface glycoprotein receptors and signaling proteins in regulating MK migration and platelet recovery after immune-induced thrombocytopenia. We show that spreading and migration of mouse primary bone marrow-derived MKs on a fibronectin matrix are abolished by the Src family kinases inhibitor PP1, the Syk kinase inhibitor R406 and the integrin alphaIIbbeta3 antagonist lotrafiban...
August 5, 2010: Blood
Jantine E Bakema, Ida H Hiemstra, Johanna Bakker, Simone de Haij, Yvonne Kok, Gosse Adema, Marjolein van Egmond, Paul J Coffer, Jan G J van de Winkel, Jeanette H W Leusen
The receptor for IgA, FcalphaRI or CD89, is expressed on myeloid cells and can trigger phagocytosis, tumor cell lysis, and release of inflammatory mediators. These functions critically depend on the associated FcR gamma-chain; however, some biological functions, like receptor internalization, are solely mediated by FcalphaRI alpha-chain. Little is known as to how FcalphaRI regulates these processes and the FcalphaRI intracellular domain does not contain recognized signalling motifs. We searched for associating proteins and identified c-Jun activating binding protein 1 (JAB1) as a binding partner specifically for FcalphaRI...
July 2010: European Journal of Immunology
Feng Liu, Dapeng Wang, Jianjun Fu, Gaoyuan Sun, Yubang Shen, Lingli Dong, Bing Zhang, Songnian Hu, Jiale Li
Grass carp is the third largest aquaculture species in global production. However, genomic research of this species has been limited. To identify immune-related genes in grass carp, a normalized full-length cDNA library was constructed from head kidney tissues, and 6432 randomly selected clones were sequenced. 5289 high quality expressed sequence tags (EST) were generated and assembled into 2687 unigenes. Among them, 1585 unigenes showed significant similarity with known sequences in public databases, whereas the remaining 1102 unigenes appeared to be novel sequences with unknown functions...
June 2010: Comparative Biochemistry and Physiology. Part D, Genomics & Proteomics
Tadayuki Yago, Bojing Shao, Jonathan J Miner, Longbiao Yao, Arkadiusz G Klopocki, Kenichiro Maeda, K Mark Coggeshall, Rodger P McEver
In inflamed venules, neutrophils rolling on E-selectin induce integrin alpha(L)beta(2)-dependent slow rolling on intercellular adhesion molecule-1 by activating Src family kinases (SFKs), DAP12 and Fc receptor-gamma (FcRgamma), spleen tyrosine kinase (Syk), and p38. E-selectin signaling cooperates with chemokine signaling to recruit neutrophils into tissues. Previous studies identified P-selectin glycoprotein ligand-1 (PSGL-1) as the essential E-selectin ligand and Fgr as the only SFK that initiate signaling to slow rolling...
July 22, 2010: Blood
Edwin Leeansyah, Jingling Zhou, Geza Paukovics, Sharon R Lewin, Suzanne M Crowe, Anthony Jaworowski
BACKGROUND: FcRgamma is an immunoreceptor tyrosine-based activation motif (ITAM)-signalling protein essential for immunoreceptor signaling and monocyte, macrophage and NK cell function. Previous study from our laboratory showed that FcRgamma is down-regulated in HIV-infected macrophages in vitro. FcRgamma expression in immune cells present in HIV-infected individuals is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We compared FcRgamma expression in peripheral blood mononuclear cells isolated from HIV-1-infected individuals receiving combination antiretroviral therapy and healthy, HIV-1-uninfected individuals...
2010: PloS One
Paul A Monach, Peter A Nigrovic, Mei Chen, Hanno Hock, David M Lee, Christophe Benoist, Diane Mathis
OBJECTIVE: Neutrophils represent a prominent component of inflammatory joint effusions and are required for synovial inflammation in mouse models, but the mechanisms are poorly understood. In this study, we developed a system with which to test the importance of the production of specific factors by neutrophils in a mouse model of arthritis. METHODS: Neutrophil-deficient Gfi-1(-/-) mice were administered sublethal doses of radiation and were then engrafted with donor bone marrow cells (BMCs), which resulted in the production of mature neutrophils within 2 weeks...
March 2010: Arthritis and Rheumatism
Hanne Schoenen, Barbara Bodendorfer, Kelly Hitchens, Silvia Manzanero, Kerstin Werninghaus, Falk Nimmerjahn, Else Marie Agger, Steffen Stenger, Peter Andersen, Jürgen Ruland, Gordon D Brown, Christine Wells, Roland Lang
The mycobacterial cord factor trehalose-6,6-dimycolate (TDM) and its synthetic analog trehalose-6,6-dibehenate (TDB) are potent adjuvants for Th1/Th17 vaccination that activate Syk-Card9 signaling in APCs. In this study, we have further investigated the molecular mechanism of innate immune activation by TDM and TDB. The Syk-coupling adapter protein FcRgamma was essential for macrophage activation and Th17 adjuvanticity. The FcRgamma-associated C-type lectin receptor Mincle was expressed in macrophages and upregulated by TDM and TDB...
March 15, 2010: Journal of Immunology: Official Journal of the American Association of Immunologists
Alice Y Pollitt, Beata Grygielska, Bertrand Leblond, Laurent Désiré, Johannes A Eble, Steve P Watson
The C-type lectin-like receptor 2 (CLEC-2) activates platelets through Src and Syk tyrosine kinases via a single cytoplasmic YxxL motif known as a hem immunoreceptor tyrosine-based activation motif (hemITAM). Here, we demonstrate using sucrose gradient ultracentrifugation and methyl-beta-cyclodextrin treatment that CLEC-2 translocates to lipid rafts upon ligand engagement and that translocation is essential for hemITAM phosphorylation and signal initiation. HemITAM phosphorylation, but not translocation, is also critically dependent on actin polymerization, Rac1 activation, and release of ADP and thromboxane A(2) (TxA(2))...
April 8, 2010: Blood
Pauline Andreu, Magnus Johansson, Nesrine I Affara, Ferdinando Pucci, Tingting Tan, Simon Junankar, Lidiya Korets, Julia Lam, David Tawfik, David G DeNardo, Luigi Naldini, Karin E de Visser, Michele De Palma, Lisa M Coussens
Chronically activated leukocytes recruited to premalignant tissues functionally contribute to cancer development; however, mechanisms underlying pro- versus anti-tumor programming of neoplastic tissues by immune cells remain obscure. Using the K14-HPV16 mouse model of squamous carcinogenesis, we report that B cells and humoral immunity foster cancer development by activating Fcgamma receptors (FcgammaRs) on resident and recruited myeloid cells. Stromal accumulation of autoantibodies in premalignant skin, through their interaction with activating FcgammaRs, regulate recruitment, composition, and bioeffector functions of leukocytes in neoplastic tissue, which in turn promote neoplastic progression and subsequent carcinoma development...
February 17, 2010: Cancer Cell
Sandrine Daubeuf, Anne Aucher, Christine Bordier, Audrey Salles, Laurent Serre, Gérald Gaibelet, Jean-Charles Faye, Gilles Favre, Etienne Joly, Denis Hudrisier
T and B cells capture antigens via membrane fragments of antigen presenting cells (APC) in a process termed trogocytosis. Whether (and how) a preferential transfer of some APC components occurs during trogocytosis is still largely unknown. We analyzed the transfer onto murine T and B cells of a large panel of fluorescent proteins with different intra-cellular localizations in the APC or various types of anchors in the plasma membrane (PM). Only the latter were transferred by trogocytosis, albeit with different efficiencies...
2010: PloS One
S Suemitsu, M Watanabe, E Yokobayashi, S Usui, T Ishikawa, Y Matsumoto, N Yamada, M Okamoto, S Kuroda
Recent studies have demonstrated the contribution of the gamma subunit of the Fc receptor of IgG (FcRgamma) to neuronal death following ischemic injury and Parkinson's disease. We examined the role of FcRgamma in hippocampal pyramidal cell death induced by kainic acid (KA). FcRgamma-deficient mice (FcRgamma-/-) and their FcRgamma+/+ littermates (wild type, B6) received an injection of KA into the dorsal hippocampus. Pyramidal cell death was quantified 24 and 72 h after the injection. The number of survived pyramidal cells was significantly larger in FcRgamma-/- mice than in B6 mice in both the CA1 and CA3...
March 31, 2010: Neuroscience
Jessica A Hamerman, Minjian Ni, Justin R Killebrew, Ching-Liang Chu, Clifford A Lowell
The adapter proteins DAP12 and FcRgamma associate with a wide spectrum of receptors in a variety of innate immune cells to mediate intracellular signaling pathways when their cognate receptor is engaged. These adapter proteins are coupled to their receptors through charged residues within the transmembrane regions of the adapter and receptor. DAP12 and FcRgamma contain specific protein domains (referred to as immunoreceptor tyrosine-based activation motifs) that serve as the substrates and docking sites for kinases, allowing amplification of intracellular signaling reactions...
November 2009: Immunological Reviews
Sergey V Guselnikov, Evdokiya S Reshetnikova, Alexander M Najakshin, Ludmila V Mechetina, Jacques Robert, Alexander V Taranin
In this study, we searched the amphibian species Xenopus laevis and Silurana (Xenopus) tropicalis for the presence of genes homologous to mammalian KIRs and avian CHIRs (KRIR family). By experimental and computational procedures, we identified four related ILR (Ig-like Receptors) genes in S. tropicalis and three in X. laevis. ILRs encode type I transmembrane receptors with 3-4 Ig-like extracellular domains. All predicted ILR proteins appear to be activating receptors. ILRs have a broad expression pattern, the gene transcripts were found in both lymphoid and non-lymphoid tissues...
March 2010: Developmental and Comparative Immunology
Denis Hudrisier, Béatrice Clemenceau, Stéphanie Balor, Sandrine Daubeuf, Eddy Magdeleine, Marc Daëron, Pierre Bruhns, Henri Vié
Intercellular transfer of cell surface proteins by trogocytosis is common and could affect T cell responses. Yet, the role of trogocytosis in T cell function is still elusive, and it is unknown whether a molecule, once captured by T cells, harbors the same biological properties as in donor APC. In this study, we showed that FcgammaR as well as the associated FcRgamma subunit could be detected at high levels on murine and human T cells after their intercellular transfer from FcgammaR-expressing APC. Capture of FcgammaR occurred during coculture of T cells with FcgammaR-expressing APC upon Ab- or Ag-mediated T cell stimulation...
November 15, 2009: Journal of Immunology: Official Journal of the American Association of Immunologists
Robin J Marjoram, Bryan Voss, Yumei Pan, S Kent Dickeson, Mary M Zutter, Heidi E Hamm, Samuel A Santoro
Thrombin and fibrillar collagen are potent activators of platelets at sites of vascular injury. Both agonists cause platelet shape change, granule secretion, and aggregation to form the primary hemostatic plug. Human platelets express two thrombin receptors, protease-activated receptors 1 and 4 (PAR1 and PAR4) and two collagen receptors, the alpha(2)beta(1) integrin (alpha(2)beta(1)) and the glycoprotein VI (GPVI)/FcRgamma chain complex. Although these receptors and their signaling mechanisms have been intensely studied, it is not known whether and how these receptors cooperate in the hemostatic function of platelets...
December 11, 2009: Journal of Biological Chemistry
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