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Suzanne S Bohlson - One of the best experts on this subject based on the ideXlab platform.
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extracellular signal regulated kinase 1 2 is required for Complement Component C1q and fibronectin dependent enhancement of fcγ receptor mediated phagocytosis in mouse and human cells
BMC Immunology, 2020Co-Authors: Emily A Willmann, Vesna Pandurovic, Anna Jokinen, Danielle Beckley, Suzanne S BohlsonAbstract:C1q is a soluble pattern recognition protein that regulates multiple leukocyte functions, and deficiency in C1q results in autoimmunity. C1q stimulates enhanced phagocytic function through multiple mechanisms including the rapid enhancement of Fcγ receptor (FcγR) -mediated phagocytosis. The molecular mechanism responsible for this rapid enhancement of phagocytic function is unknown. The purpose of this study was to investigate the molecular pathway required for C1q-dependent enhanced phagocytosis. Leukocyte associated immunoglobulin like receptor-1 (LAIR-1) is a receptor that mediates C1q-dependent activation of leukocytes; however, using LAIR-1 deficient mouse bone marrow derived macrophages (BMDM), we demonstrated that LAIR-1 was not required for C1q-dependent enhanced FcγR-mediated phagocytosis. A phospho-kinase array identified extracellular signal-regulated kinase (ERK) 1/2 as dysregulated following activation with C1q. Validation of the array in BMDM and the human monocyte cell line THP-1 demonstrated a decrease in basal ERK1/2 phosphorylation in C1q-stimulated cells compared to control cells. However, subsequent stimulation with immune complexes stimulated rapid upregulation of phosphorylation. The extracellular matrix protein fibronectin regulates enhanced phagocytic activity in macrophages similar to C1q, and both C1q and fibronectin-dependent enhanced phagocytosis required ERK1/2 since both were blocked by pharmacologic inhibition of ERK1/2. Furthermore, diminished C1q-dependent ERK1/2 phosphorylation was sustained after four-hour treatment with lipopolysaccharide and correlated with a significant reduction in TNFα production. These data demonstrate that C1q and fibronectin utilize a similar ERK1/2-dependent mechanism for enhanced phagocytosis, which should lead to development of novel approaches to modulate C1q-dependent regulation of macrophage activation, inflammation and autoimmunity.
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Complement Component C1q programs a pro efferocytic phenotype while limiting tnfα production in primary mouse and human macrophages
Frontiers in Immunology, 2016Co-Authors: Holly J Hulsebus, Sean D Oconner, Emily M Smith, Chunfa Jie, Suzanne S BohlsonAbstract:Deficiency in Complement Component C1q is associated with an inability to clear apoptotic cells (efferocytosis) and aberrant inflammation in lupus, and identification of the pathways involved in these processes should reveal important regulatory mechanisms in lupus and other autoimmune or inflammatory diseases. In this study, C1q-dependent regulation of TNFα/IL-6 expression and efferocytosis was investigated using primary mouse bone marrow derived macrophages, and human monocyte derived macrophages. C1q downregulated LPS-dependent TNFα production in mouse and human macrophages. While prolonged stimulation with C1q (18 hours) was required to elicit a dampening of TNFα production from mouse macrophages, the human macrophages responded to C1q with immediate downregulation of TNFα. IL-6 production was unchanged in mouse and upregulated by human macrophages following prolonged stimulation with C1q. Our previous studies indicated that C1q programmed enhanced efferocytosis in mouse macrophages by enhancing expression of Mer tyrosine kinase and its ligand Gas6, a receptor-ligand pair that also inhibits proinflammatory signaling. Here we demonstrated that C1q-dependent programming of human macrophage efferocytosis required protein synthesis, however neither Mer nor the related receptor Axl were upregulated in human cells. In addition, while the C1q-collagen-like tails are sufficient for promoting C1q-dependent phagocytosis of antibody coated targets, the C1q-tails failed to program enhanced efferocytosis or dampen TNFα production. These data further elucidate the mechanisms by which C1q regulates proinflammatory signaling and efferocytosis in macrophages, functions that are likely to influence the progression of autoimmunity and chronic inflammation.
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Complement Component C1q regulates macrophage expression of mer tyrosine kinase to promote clearance of apoptotic cells
Journal of Immunology, 2012Co-Authors: Manuel D Galvan, Deborah B Foreman, Erliang Zeng, John C Tan, Suzanne S BohlsonAbstract:Failure to efficiently clear apoptotic cells is linked to defects in development and the onset of autoimmunity. Complement Component C1q is required for efficient engulfment of apoptotic cells in mice and humans; however, the molecular mechanisms leading to C1q-dependent engulfment are not fully understood. In this study, we used primary mouse macrophages to identify and characterize a novel molecular mechanism for macrophage-mediated C1q-dependent engulfment of apoptotic cells. We found that macrophage activation with C1q resulted in cycloheximide-sensitive enhanced engulfment, indicating a requirement for de novo protein synthesis. To investigate the cycloheximide-sensitive pathway, C1q-elicited macrophage transcripts were identified by microarray. C1q triggered the expression of Mer tyrosine kinase (Mer) and the Mer ligand growth arrest-specific 6: a receptor–ligand pair that mediates clearance of apoptotic cells. Full-length native C1q, and not the collagen-like tail or heat-denatured protein, stimulated Mer expression. This novel pathway is specific to C1q because mannose-binding lectin, a related collectin, failed to upregulate Mer expression and function. Soluble Mer-Fc fusion protein inhibited C1q-dependent engulfment of apoptotic cells, indicating a requirement for Mer. Moreover, Mer-deficient macrophages failed to respond to C1q with enhanced engulfment. Our results suggest that C1q elicits a macrophage phenotype specifically tailored for apoptotic cell clearance, and these data are consistent with the established requirement for C1q in prevention of autoimmunity.
Andrea J Tenner - One of the best experts on this subject based on the ideXlab platform.
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sialylation of neurites inhibits Complement mediated macrophage removal in a human macrophage neuron co culture system
Glia, 2016Co-Authors: Bettina Linnartzgerlach, Andrea J Tenner, Christine Schuy, Anahita Shahraz, Harald NeumannAbstract:The Complement system has been implicated in the removal of dysfunctional synapses and neurites during development and in disease processes in the mouse, but it is unclear how far the mouse data can be transferred to humans. Here, we co-cultured macrophages derived from human THP1 monocytes and neurons derived from human induced pluripotent stem cells, to study the role of the Complement system in a human model. Components of the Complement system were expressed by the human macrophages and human neuronal culture, while receptors of the Complement cascade were expressed by human macrophages as shown via gene transcript analysis and flow cytometry. We mimicked pathological conditions leading to an altered glycocalyx by treatment of human neurons with sialidases. Desialylated human neurites were opsonized by the Complement Component C1q. Furthermore, human neurites with an intact sialic acid cap remained untouched, while desialylated human neurites were removed and ingested by human macrophages. While blockage of the Complement receptor 1 (CD35) had no effect, blockage of CD11b as part of the Complement receptor 3 (CR3) reversed the effect on macrophage phagocytosis of desialylated human neurites. Data demonstrate that in the human system sialylation of the neuronal glycocalyx serves as an inhibitory flag for Complement binding and CR3-mediated phagocytosis by macrophages.
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Complement Component C1q inhibits β amyloid and serum amyloid p induced neurotoxicity via caspase and calpain independent mechanisms
Journal of Neurochemistry, 2007Co-Authors: Karntipa Pisalyaput, Andrea J TennerAbstract:Alzheimer’s disease is a neurodegenerative disorder characterized by neuronal loss, β-amyloid (Aβ) plaques, and neurofibrillary tangles. Complement protein C1q has been found associated with fibrillar Aβ deposits, however the exact contributions of C1q to Alzheimer’s disease is still unknown. There is evidence that C1q, as an initiator of the inflammatory Complement cascade, may accelerate disease progression. However, neuronal C1q synthesis is induced after injury/infection suggesting that it may be a beneficial response to injury. In this study, we report that C1q enhances the viability of neurons in culture and protects neurons against Aβ- and serum amyloid P (SAP)-induced neurotoxicity. Investigation of potential signaling pathways indicates that caspase and calpain are activated by Aβ, but C1q had no effect on either of these pathways. Interestingly, SAP did not induce caspase and calpain activation, suggesting that C1q neuroprotection is in distinct from caspase and calpain pathways. In contrast to Aβ- and SAP-induced neurotoxicity, neurotoxicity induced by etoposide or FCCP was unaffected by the addition of C1q, indicating pathway selectivity for C1q neuroprotection. These data support a neuroprotective role for C1q which should be further investigated to uncover mechanisms which may be therapeutically targeted to slow neurodegeneration via direct inhibition of neuronal loss.
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Complement Component C1q modulates the phagocytosis of abeta by microglia
Experimental Neurology, 2000Co-Authors: Scott D Webster, Austin J Yang, Larry Margol, William Garzonrodriguez, Charles G Glabe, Andrea J TennerAbstract:Recent studies showing that microglia internalize the amyloid beta-peptide (Abeta) suggest that these cells have the potential for clearing Abeta deposits in Alzheimer's disease, and mechanisms that regulate the removal of Abeta may therefore be of clinical interest. Previous studies from this laboratory showing that C1q enhances phagocytosis of cellular targets by rat microglia prompted the current investigations characterizing the effects of C1q on microglial phagocytosis of Abeta. Microglia were shown to phagocytose Abeta1-42, in agreement with observations of other investigators. Uptake of Abeta1-42 was observed for concentrations of 5-50 microM, and phagocytosis of peptides containing (14)C or fluorescein (FM) labels was not affected by the interaction of microglia with C1q-coated surfaces. However, inclusion of C1q (125 nM-1.4 microM) in solutions of 50 microM Abeta1-42 inhibited the uptake of (14)C-Abeta1-42 and FM-Abeta1-42, suggesting that C1q blocks the interaction of Abeta with microglia. Uptake of Abeta was partially blocked by the scavenger receptor ligands polyinosinic acid and maleylated BSA. Inhibition of Abeta uptake by C1q may contribute to the accumulation of fibrillar, C1q-containing plaques that occurs in parallel with disease progression. These data suggest that mechanisms which interfere with the binding of C1q to Abeta may be of therapeutic value both through inhibition of the inflammatory events resulting from Complement activation and via altered access of Abeta sites necessary for ingestion by microglia.
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localization of the site on the Complement Component C1q required for the stimulation of neutrophil superoxide production
Journal of Biological Chemistry, 1995Co-Authors: S Ruiz, Agnes Henschenedman, Andrea J TennerAbstract:C1q, the recognition subunit of the classical Complement pathway, interacts with specific cell surface molecules via its collagen-like region (C1q-CLR). This binding of C1q to neutrophils triggers the generation of toxic oxygen species. To identify the site on C1q that interacts with the neutrophil C1q receptor, C1q was isolated, digested with pepsin to produce C1q-CLR, and further cleaved with either trypsin or endoproteinase Lys-C. The resulting fragments were separated by gel filtration chromatography and analyzed functionally (activation of the respiratory burst in neutrophils) and structurally. Cleavage of C1q-CLR with endoproteinase Lys-C did not alter its ability to trigger neutrophil superoxide production. However, when C1q-CLR was incubated with trypsin under conditions permitting optimal cleavage, the ability of C1q-CLR to stimulate superoxide production in neutrophils was completely abrogated. Fractionation of the digests obtained with the two enzymes and identification by amino acid sequencing permitted localization of the receptor interaction site to a specific region of the C1q-CLR. Circular dichroism analyses demonstrated that cleavage by trypsin does not denature the remaining uncleaved collagen-like structure, suggesting that after trypsin treatment, the loss of activity was not due to a loss of secondary structure of the molecule. However, irreversible heat denaturation of C1q-CLR also abrogated all activity. Thus, a specific conformation conferred by the collagen triple helix constitutes the functional receptor interaction site. These data should direct the design of future specific therapeutic reagents to selectively modulate this response.
Francesco Carlucci - One of the best experts on this subject based on the ideXlab platform.
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C1q modulates the response to tlr7 stimulation by pristane primed macrophages implications for pristane induced lupus
Journal of Immunology, 2016Co-Authors: Francesco Carlucci, Attia Ishaque, Guang Sheng Ling, Marta Szajna, Terence H Cook, Ann Sandison, Philippe Donatien, Marina BottoAbstract:The Complement Component C1q is known to play a controversial role in the pathogenesis of systemic lupus erythematosus, but the underlying mechanisms remain poorly understood. Intraperitoneal injection of pristane induces a lupus-like syndrome whose pathogenesis implicates the secretion of type I IFN by CD11b + Ly6C high inflammatory monocytes in a TLR7-dependent fashion. C1q was also shown to influence the secretion of IFN-α. In this study, we explored whether C1q deficiency could affect pristane-induced lupus. Surprisingly, C1qa −/− mice developed lower titers of circulating Abs and milder arthritis compared with the controls. In keeping with the clinical scores, 2 wk after pristane injection the peritoneal recruitment of CD11b + Ly6C high inflammatory monocytes in C1qa −/− mice was impaired. Furthermore, C1q-deficient pristane-primed resident peritoneal macrophages secreted significantly less CCL3, CCL2, CXCL1, and IL-6 when stimulated in vitro with TLR7 ligand. Replenishing C1q in vivo during the pristane-priming phase rectified this defect. Conversely, pristane-primed macrophages from C3-deficient mice did not show impaired cytokine production. These findings demonstrate that C1q deficiency impairs the TLR7-dependent chemokine production by pristane-primed peritoneal macrophages and suggest that C1q, and not C3, is involved in the handling of pristane by phagocytic cells, which is required to trigger disease in this model.
Berhane Ghebrehiwet - One of the best experts on this subject based on the ideXlab platform.
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Cossart P: gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogene
2016Co-Authors: Laurence Braun, Berhane Ghebrehiwet, Pascale CossartAbstract:InlB is a Listeria monocytogenes protein that promotes entry of the bacterium into mammalian cells by stimu-lating tyrosine phosphorylation of the adaptor proteins Gab1, Cbl and Shc, and activation of phosphatidyl-inositol (PI) 3-kinase. Using affinity chromatography and enzyme-linked immunosorbent assay, we demon-strate a direct interaction between InlB and the mammalian protein gC1q-R, the receptor of the globu-lar part of the Complement Component C1q. Soluble C1q or anti-gC1q-R antibodies impair InlB-mediated entry. Transient transfection of GPC16 cells, which are non-permissive to InlB-mediated entry, with a plasmid-expressing human gC1q-R promotes entry of InlB-coated beads. Furthermore, several experiments indicate that membrane recruitment and activation of PI 3-kinase involve an InlB–gC1q-R interaction and that gC1q-R associates with Gab1 upon stimulation of Vero cells with InlB. Thus, gC1q-R constitutes a cellular receptor involved in InlB-mediated activation of PI 3-kinase and tyrosine phosphorylation of the adaptor protein Gab1. After E-cadherin, the receptor for internalin, gC1q-R is the second identified mammalian receptor promoting entry of L.monocytogenes into mammalian cells
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chemotaxis of human monocyte derived dendritic cells to Complement Component C1q is mediated by the receptors gC1qr and cC1qr
Molecular Immunology, 2006Co-Authors: Zsuzsa Vegh, Richard R Kew, Barry L Gruber, Berhane GhebrehiwetAbstract:Dendritic cells (DCs) are recruited to inflammatory sites where they phagocytose and process antigens for subsequent presentation to the T lymphocytes in the lymphoid tissue. Several leukocyte chemoattractants and their specific receptors have been shown to induce the migration of DC. The Complement protein C1q has multiple immune functions including acting as a chemoattractant for neutrophils, eosinophils and mast cells. Therefore, the objective of this study was to determine if soluble C1q can induce chemotaxis of DC. Culturing cells in GM-CSF and IL-4 for 5 to 7 days generated human monocyte-derived DCs. In addition, LPS was added from day 5 to 7 to induce DC maturation. Cells were classified as either immature or mature DC by assessing the cell surface markers by flow cytometry, phagocytosis of dextran-FITC and T cell proliferation in an allogenic MLR. Immature DCs express the C1q receptors (C1qR), gC1qR and cC1qR/CR and, accordingly, display a vigorous migratory response to soluble C1q with maximal cell movement observed at 10-50nM. In contrast, mature DCs neither express C1qR nor do move to a gradient of soluble C1q. Varying the concentration gradient of C1q (checkerboard assay) showed that the protein largely induces a chemotactic response. Finally, blocking gC1qR and cC1qR/CR by using specific antibodies abolished the chemotactic response to C1q but had no effect on a different chemoattractant C5a. These results clearly demonstrate that C1q functions as a chemotactic factor for immature DC, and migration is mediated through ligation of both gC1qR and cC1qR/CR.
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Complement Component C1q induces endothelial cell adhesion and spreading through a docking signaling partnership of C1q receptors and integrins
International Immunopharmacology, 2003Co-Authors: Berhane Ghebrehiwet, Xiaodong Feng, Rajeev Kumar, Ellinor I B PeerschkeAbstract:Abstract The interaction of C1q with endothelial cells elicits a multiplicity of biologic responses. Although these specific responses are thought to be mediated by the interaction of C1q with proteins of the endothelial cell surface, the molecular identity of the participant(s) has not been clearly defined. In this study, we examined the role of two C1q-binding proteins, cC1q-R/CR and gC1q-R/p33, on C1q-mediated adhesion and spreading of human dermal microvascular endothelial cells (HDMVECs). A specific and dose-dependent adhesion and spreading was observed when HDMVECs were cultured in microtiter plate wells coated with concentrations of C1q ranging from 0 to 50 μg/ml. The extent of adhesion and spreading was similar to the adhesion seen on collagen-coated wells. Furthermore, the effect of C1q was mimicked by either polyclonal anti-cC1q-R or mAb 60.11, but not with isotype- and species-matched control IgG. More importantly, however, a 100% inhibition of spreading but not adhesion to C1q-coated wells was observed when HDMVECs were cultured in the presence of 30 mM of the peptide GRRGDSP but not GRRGESP. Furthermore, while anti-β1 integrin antibody blocked adhesion and spreading, antiα5 integrin only blocked spreading. Since earlier studies have shown that zinc induces the exposure of hydrophobic sites in the C-terminus of gC1q-R including the putative high-molecular weight kininogen (HK)-binding site corresponding to residues 204–218, we also examined the effect of zinc on antibody binding to cell surface gC1q-R. Flow cytometric data show that the binding of mAb 74.5.2, which recognizes residues 204–218, is greatly enhanced when endothelial cells were incubated in the presence of 50 μM zinc. In summary, our data show that: (a) C1q-mediated endothelial cell adhesion and spreading requires the cooperation of both C1q receptors and 1 integrins, and possibly other membrane-spanning molecules, and (b) zinc can induce the exposure of hydrophobic sites in the C-terminal domain of gC1q-R allowing a more efficient binding of mAb 74.5.2 and HK.
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gC1q r p32 a C1q binding protein is a receptor for the inlb invasion protein of listeria monocytogenes
The EMBO Journal, 2000Co-Authors: Laurence Braun, Berhane Ghebrehiwet, Pascale CossartAbstract:InlB is a Listeria monocytogenes protein that promotes entry of the bacterium into mammalian cells by stimulating tyrosine phosphorylation of the adaptor proteins Gab1, Cbl and Shc, and activation of phosphatidylinositol (PI) 3‐kinase. Using affinity chromatography and enzyme‐linked immunosorbent assay, we demonstrate a direct interaction between InlB and the mammalian protein gC1q‐R, the receptor of the globular part of the Complement Component C1q. Soluble C1q or anti‐gC1q‐R antibodies impair InlB‐mediated entry. Transient transfection of GPC16 cells, which are non‐permissive to InlB‐mediated entry, with a plasmid‐expressing human gC1q‐R promotes entry of InlB‐coated beads. Furthermore, several experiments indicate that membrane recruitment and activation of PI 3‐kinase involve an InlB–gC1q‐R interaction and that gC1q‐R associates with Gab1 upon stimulation of Vero cells with InlB. Thus, gC1q‐R constitutes a cellular receptor involved in InlB‐mediated activation of PI 3‐kinase and tyrosine phosphorylation of the adaptor protein Gab1. After E‐cadherin, the receptor for internalin, gC1q‐R is the second identified mammalian receptor promoting entry of L.monocytogenes into mammalian cells.
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up regulation of endothelial cell binding proteins receptors for Complement Component C1q by inflammatory cytokines
Journal of Laboratory and Clinical Medicine, 1999Co-Authors: Weixing Guo, Berhane Ghebrehiwet, Babette B Weksler, Karin Schweitzer, Ellinor I B PeerschkeAbstract:Abstract Endothelial cells express a variety of receptor systems involved in humoral defense, including receptors for the collagen-like and globular domains of the Complement Component C1q, designated cC1qR and gC1qR, respectively. In the present study a microvascular endothelial cell line was used to test the hypothesis that expression of these C1q-binding proteins may be affected by vascular inflammatory reactions. The results demonstrate that the expression of both cC1qR and gC1qR by bone marrow vascular endothelial cells is up-regulated by inflammatory mediators, interferon–γ, tumor necrosis factor-α, and lipopolysaccharide (Escherichia coli , 055:B5) in a dose- and time-dependent manner, as detected by enzyme-linked immunosorbent assay. cC1qR and gC1qR expression increased significantly (P
Marina Botto - One of the best experts on this subject based on the ideXlab platform.
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C1q modulates the response to tlr7 stimulation by pristane primed macrophages implications for pristane induced lupus
Journal of Immunology, 2016Co-Authors: Francesco Carlucci, Attia Ishaque, Guang Sheng Ling, Marta Szajna, Terence H Cook, Ann Sandison, Philippe Donatien, Marina BottoAbstract:The Complement Component C1q is known to play a controversial role in the pathogenesis of systemic lupus erythematosus, but the underlying mechanisms remain poorly understood. Intraperitoneal injection of pristane induces a lupus-like syndrome whose pathogenesis implicates the secretion of type I IFN by CD11b + Ly6C high inflammatory monocytes in a TLR7-dependent fashion. C1q was also shown to influence the secretion of IFN-α. In this study, we explored whether C1q deficiency could affect pristane-induced lupus. Surprisingly, C1qa −/− mice developed lower titers of circulating Abs and milder arthritis compared with the controls. In keeping with the clinical scores, 2 wk after pristane injection the peritoneal recruitment of CD11b + Ly6C high inflammatory monocytes in C1qa −/− mice was impaired. Furthermore, C1q-deficient pristane-primed resident peritoneal macrophages secreted significantly less CCL3, CCL2, CXCL1, and IL-6 when stimulated in vitro with TLR7 ligand. Replenishing C1q in vivo during the pristane-priming phase rectified this defect. Conversely, pristane-primed macrophages from C3-deficient mice did not show impaired cytokine production. These findings demonstrate that C1q deficiency impairs the TLR7-dependent chemokine production by pristane-primed peritoneal macrophages and suggest that C1q, and not C3, is involved in the handling of pristane by phagocytic cells, which is required to trigger disease in this model.
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Complement Component C1q mediates mitochondria driven oxidative stress in neonatal hypoxic ischemic brain injury
The Journal of Neuroscience, 2010Co-Authors: Vadim S Ten, Marina Botto, Jun Yao, Veniamin Ratner, Sergey A Sosunov, Deborah A Fraser, Baalasubramanian Sivasankar, Paul B Morgan, Samuel C Silverstein, Raymond I StarkAbstract:Hypoxic–ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia–ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal Complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia–ischemia. Only C1q−/− mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q−/− brain mitochondria and preserved activity of the respiratory chain. Compared with C1q+/+ neurons, cortical C1q−/− neurons exhibited resistance to oxygen–glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q−/− neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q Component of Complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal Complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal Complement activation.