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Colin R Andrew, Olga N Petrova, Isabelle Lamarre, Jean-Christophe Lambry, Fabrice Rappaport, Michel Negrerie
Nitric oxide (NO) sensors are heme proteins which may also bind CO and O2. Control of heme-gas affinity and their discrimination are achieved by the structural properties and reactivity of the heme and its distal and proximal environments, leading to several energy barriers. In the bacterial NO-sensor cytochrome c' from Alcaligenes xylosoxidans (AXCP), the single Leu16Ala distal mutation boosts the affinity for gas ligands by a remarkable 106-108-fold, transforming AXCP from one of the lowest affinity gas binding proteins to one of the highest...
October 6, 2016: ACS Chemical Biology
Jan-Michael Abicht, Ioannis Kourtzelis, Bruno Reichart, Sophia Koutsogiannaki, Alexandra Primikyri, John D Lambris, Triantafyllos Chavakis, Lesca Holdt, Alexander Kind, Sonja Guethoff, Tanja Mayr
BACKGROUND: The complement system plays a crucial role in acute xenogeneic reactions after cardiac transplantation. We used an ex vivo perfusion model to investigate the effect of Cp40, a compstatin analog and potent inhibitor of complement at the level of C3. METHODS: Fifteen wild-type pig hearts were explanted, cardiopleged, and reperfused ex vivo after 150 minutes of cold ischemia. Hearts were challenged in a biventricular working heart mode to evaluate cardiac perfusion and function...
September 27, 2016: Xenotransplantation
Margaret A Lindorfer, Erika M Cook, Edimara S Reis, Daniel Ricklin, Antonio M Risitano, John D Lambris, Ronald P Taylor
During malarial anemia, 20 uninfected red blood cells (RBCs) are destroyed for every RBC infected by Plasmodium falciparum (Pf). Increasing evidence indicates an important role for complement in destruction of uninfected RBCs. Products of RBC lysis induced by Pf, including the digestive vacuole and hematin, activate complement and promote C3 fragment deposition on uninfected RBCs. C3-opsonized cells are then subject to extravascular destruction mediated by fixed tissue macrophages which express receptors for C3 fragments...
October 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Stephanie K Doerner, Edimara S Reis, Elaine S Leung, Justine S Ko, Jason D Heaney, Nathan A Berger, John D Lambris, Joseph H Nadeau
: Obesity and related metabolic disturbances are closely associated with pathologies that represent a significant burden to global health. Epidemiological and molecular evidence links obesity and metabolic status with inflammation and increased risk of cancer. Here, using a mouse model of intestinal neoplasia and strains that are susceptible or resistant to diet-induced obesity, it is demonstrated that high-fat diet-induced inflammation, rather than obesity or metabolic status, is associated with increased intestinal neoplasia...
October 2016: Molecular Cancer Research: MCR
Daniel Ricklin, John D Lambris
No abstract text is available yet for this article.
June 2016: Seminars in Immunology
Jun S Min, Robert A DeAngelis, Edimara S Reis, Shakti Gupta, Mano R Maurya, Charles Evans, Arun Das, Charles Burant, John D Lambris, Shankar Subramaniam
Liver regeneration is a well-orchestrated process in the liver that allows mature hepatocytes to reenter the cell cycle to proliferate and replace lost or damaged cells. This process is often impaired in fatty or diseased livers, leading to cirrhosis and other deleterious phenotypes. Prior research has established the role of the complement system and its effector proteins in the progression of liver regeneration; however, a detailed mechanistic understanding of the involvement of complement in regeneration is yet to be established...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Dimitrios C Mastellos, Edimara S Reis, Despina Yancopoulou, George Hajishengallis, Daniel Ricklin, John D Lambris
Complement dysregulation is increasingly recognized as an important pathogenic driver in a number of clinical disorders. Complement-triggered pathways intertwine with key inflammatory and tissue destructive processes that can either increase the risk of disease or exacerbate pathology in acute or chronic conditions. The launch of the first complement-targeted drugs in the clinic has undeniably stirred the field of complement therapeutic design, providing new insights into complement's contribution to disease pathogenesis and also helping to leverage a more personalized, comprehensive approach to patient management...
October 2016: Immunobiology
Daniel Ricklin, John D Lambris
The complement system is a powerful effector arm of innate immunity that typically confers protection from microbial intruders and accumulating debris. In many clinical situations, however, the defensive functions of complement can turn against host cells and induce or exacerbate immune, inflammatory, and degenerative conditions. Although the value of inhibiting complement in a therapeutic context has long been recognized, bringing complement-targeted drugs into clinical use has proved challenging. This important milestone was finally reached a decade ago, yet the clinical availability of complement inhibitors has remained limited...
June 2016: Seminars in Immunology
Daniel Ricklin, Edimara S Reis, John D Lambris
Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris - such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways - can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases...
July 2016: Nature Reviews. Nephrology
Adam Z Blatt, Gurpanna Saggu, Koustubh V Kulkarni, Claudio Cortes, Joshua M Thurman, Daniel Ricklin, John D Lambris, Jesus G Valenzuela, Viviana P Ferreira
Enhanced levels of platelet/granulocyte aggregates (PGAs) are found in patients suffering from many different inflammatory vascular diseases, and their formation in animal models of vascular disease is associated with increased thromboinflammation and worsened outcomes. The complement system, a part of the innate immune system, influences PGA formation, but the mechanisms for its effects are unknown. In this study, we have defined complement-mediated mechanisms that enhance PGA formation in human whole blood stimulated with thrombin receptor-activating peptide (TRAP) using ex vivo flow cytometry assays...
June 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
George Hajishengallis, Jennifer L Krauss, Ravi Jotwani, John D Lambris
The complement system plays a central role in immunity and inflammation, although certain pathogens can exploit complement to undermine protective immunity. In this context, the periodontal keystone pathogen Porphyromonas gingivalis (Pg) was previously shown by our group to evade killing by neutrophils or macrophages through exploitation of complement C5a receptor 1 (C5aR1) and complement receptor-3 (CR3). Here, we examined whether Pg uses complement receptors to also subvert killing by dendritic cells. In line with earlier independent studies, intracellular viable Pg bacteria could be recovered from mouse bone marrow-derived dendritic cells (BMDC) or human monocyte-derived dendritic cells (MDDC) exposed to the pathogen...
April 15, 2016: Molecular Oral Microbiology
Florence Broders-Bondon, Perrine Paul-Gilloteaux, Elodie Gazquez, Julie Heysch, Matthieu Piel, Roberto Mayor, John D Lambris, Sylvie Dufour
We analyzed the cellular and molecular mechanisms governing the adhesive and migratory behavior of enteric neural crest cells (ENCCs) during their collective migration within the developing mouse gut. We aimed to decipher the role of the complement anaphylatoxin C3a during this process, because this well-known immune system attractant has been implicated in cephalic NCC co-attraction, a process controlling directional migration. We used the conditional Ht-PA-cre transgenic mouse model allowing a specific ablation of the N-cadherin gene and the expression of a fluorescent reporter in migratory ENCCs without affecting the central nervous system...
June 1, 2016: Developmental Biology
George Hajishengallis, Evlambia Hajishengallis, Tetsuhiro Kajikawa, Baomei Wang, Despina Yancopoulou, Daniel Ricklin, John D Lambris
Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss...
June 2016: Seminars in Immunology
Federico Forneris, Jin Wu, Xiaoguang Xue, Daniel Ricklin, Zhuoer Lin, Georgia Sfyroera, Apostolia Tzekou, Elena Volokhina, Joke Cm Granneman, Richard Hauhart, Paula Bertram, M Kathryn Liszewski, John P Atkinson, John D Lambris, Piet Gros
Regulators of complement activation (RCA) inhibit complement-induced immune responses on healthy host tissues. We present crystal structures of human RCA (MCP, DAF, and CR1) and a smallpox virus homolog (SPICE) bound to complement component C3b. Our structural data reveal that up to four consecutive homologous CCP domains (i-iv), responsible for inhibition, bind in the same orientation and extended arrangement at a shared binding platform on C3b. Large sequence variations in CCP domains explain the diverse C3b-binding patterns, with limited or no contribution of some individual domains, while all regulators show extensive contacts with C3b for the domains at the third site...
May 17, 2016: EMBO Journal
Alice Gustavsen, Stig Nymo, Anne Landsem, Dorte Christiansen, Liv Ryan, Harald Husebye, Corinna Lau, Søren E Pischke, John D Lambris, Terje Espevik, Tom E Mollnes
BACKGROUND: Single inhibition of the Toll-like receptor 4 (TLR4)-MD2 complex failed in treatment of sepsis. CD14 is a coreceptor for several TLRs, including TLR4 and TLR2. The aim of this study was to investigate the effect of single TLR4-MD2 inhibition by using eritoran, compared with the effect of CD14 inhibition alone and combined with the C3 complement inhibitor compstatin (Cp40), on the bacteria-induced inflammatory response in human whole blood. METHODS: Cytokines were measured by multiplex technology, and leukocyte activation markers CD11b and CD35 were measured by flow cytometry...
July 1, 2016: Journal of Infectious Diseases
Christoph Q Schmidt, Markus J Harder, Eva-Maria Nichols, Mario Hebecker, Markus Anliker, Britta Höchsmann, Thomas Simmet, Ádám I Csincsi, Barbara Uzonyi, Isabel Y Pappworth, Daniel Ricklin, John D Lambris, Hubert Schrezenmeier, Mihály Józsi, Kevin J Marchbank
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated cell lysis due to deficiency of GPI-anchored complement regulators. Blockage of the lytic pathway by eculizumab is the only available therapy for PNH patients and shows remarkable benefits, but regularly yields PNH erythrocytes opsonized with fragments of complement protein C3, rendering such erythrocytes prone to extravascular hemolysis. This effect is associated with insufficient responsiveness seen in a subgroup of PNH patients...
April 2016: Immunobiology
Tomoki Maekawa, Ruel A Briones, Ranillo R G Resuello, Joel V Tuplano, Evlambia Hajishengallis, Tetsuhiro Kajikawa, Sophia Koutsogiannaki, Cristina A G Garcia, Daniel Ricklin, John D Lambris, George Hajishengallis
AIM: Human periodontitis is associated with overactivation of complement, which is triggered by different mechanisms converging on C3, the central hub of the system. We assessed whether the C3 inhibitor Cp40 inhibits naturally occurring periodontitis in non-human primates (NHPs). MATERIALS AND METHODS: Non-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for 6 weeks followed by a 6-week follow-up period...
March 2016: Journal of Clinical Periodontology
Jean-Christophe Lambry, Martin Stranava, Laura Lobato, Marketa Martinkova, Toru Shimizu, Ursula Liebl, Marten H Vos
An important question for the functioning of heme proteins is whether different ligands present within the protein moiety can readily exchange with heme-bound ligands. Studying the dynamics of the heme domain of the Escherichia coli sensor protein YddV upon dissociation of NO from the ferric heme by ultrafast spectroscopy, we demonstrate that when the hydrophobic leucine residue in the distal heme pocket is mutated to glycine, in a substantial fraction of the protein water replaces NO as an internal ligand in as fast as ∼4 ps...
January 7, 2016: Journal of Physical Chemistry Letters
Markus J Harder, Markus Anliker, Britta Höchsmann, Thomas Simmet, Markus Huber-Lang, Hubert Schrezenmeier, Daniel Ricklin, John D Lambris, Paul N Barlow, Christoph Q Schmidt
The serum proteins factor H (FH), consisting of 20 complement control protein modules (CCPs), and its splice product FH-like protein 1 (FHL-1; consisting of CCPs 1-7) are major regulators of the alternative pathway (AP) of complement activation. The engineered version of FH, miniFH, contains only the N- and C-terminal portions of FH linked by an optimized peptide and shows ∼ 10-fold higher ex vivo potency. We explored the hypothesis that regulatory potency is enhanced by unmasking of a ligand-binding site in the C-terminal CCPs 19-20 that is cryptic in full-length native FH...
January 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
George Kollias, John D Lambris
No abstract text is available yet for this article.
December 2015: Nature Immunology
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