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Supriya D Mahajan, Ravikumar Aalinkeel, Neil U Parikh, Alexander Jacob, Katherine Cwiklinski, Prateet Sandhu, Kevin Le, Alexander W Loftus, Stanley A Schwartz, Richard J Quigg, Jessy J Alexander
The complement system which is a critical mediator of innate immunity plays diverse roles in the neuropathogenesis of HIV-1 infection such as clearing HIV-1 and promoting productive HIV-1 replication. In the development of HIV-1 associated neurological disorders (HAND), there may be an imbalance between complement activation and regulation, which may contribute to the neuronal damage as a consequence of HIV-1 infection. It is well recognized that opiate abuse exacerbates HIV-1 neuropathology, however, little is known about the role of complement proteins in opiate induced neuromodulation, specifically in the presence of co-morbidity such as HIV-1 infection...
November 2017: Immunological Investigations
Ina V Martin, Annika Bohner, Peter Boor, Erdenechimeg Shagdarsuren, Ute Raffetseder, Frank Lammert, Jürgen Floege, Tammo Ostendorf, Susanne N Weber
Complement factor C5a has two known receptors, C5aR, which mediates proinflammatory effects, and C5L2, a potential C5a decoy receptor. We previously identified C5a/C5aR signaling as a potent profibrotic pathway in the kidney. Here we tested for the first time the role of C5L2 in renal fibrosis. In unilateral ureteral obstruction (UUO)-induced kidney fibrosis, the expression of C5aR and C5L2 increased similarly and gradually as fibrosis progressed and was particularly prominent in injured dilated tubules. Genetic deficiency of either C5aR or C5L2 significantly reduced UUO-induced tubular injury...
January 1, 2018: American Journal of Physiology. Renal Physiology
Christian M Karsten, Anna V Wiese, Fabian Mey, Julia Figge, Trent M Woodruff, Tom Reuter, Olga Scurtu, Anna Kordowski, Larissa N Almeida, Daria Briukhovetska, Katharina M Quell, Jing Sun, Fanny Ender, Inken Schmudde, Tillman Vollbrandt, Yves Laumonnier, Jörg Köhl
The biological significance of C5a receptor [(C5aR)2/C5L2], a seven-transmembrane receptor binding C5a and C5adesArg, remains ill-defined. Specific ligation of C5aR2 inhibits C5a-induced ERK1/2 activation, strengthening the view that C5aR2 regulates C5aR1-mediated effector functions. Although C5aR2 and C5aR1 are often coexpressed, a detailed picture of C5aR2 expression in murine cells and tissues is still lacking. To close this gap, we generated a floxed tandem dye (td)Tomato-C5aR2 knock-in mouse that we used to track C5aR2 expression in tissue-residing and circulating immune cells...
November 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Jing Wu, Zhou-Yang Jiao, Rui-Zhen Li, Hui-Ling Lu, Hao-Hao Zhang, Katherine Cianflone
Acylation-stimulating protein (ASP), produced through activation of the alternative complement immune system, modulates lipid metabolism. Using a trans-well co-culture cell model, the mitigating role of α7-nicotinic acetylcholine receptor (α7nAChR)-mediated cholinergic pathway on ASP resistance was evaluated. ASP signaling in adipocytes via its receptor C5L2 and signaling intermediates Gαq, Gβ, phosphorylated protein kinase C-α, and protein kinase C-ζ were markedly suppressed in the presence of TNFα or medium from palmitate-treated RAW264...
May 2017: Experimental Biology and Medicine
Philipp Janesch, Harald Rouha, Susanne Weber, Stefan Malafa, Karin Gross, Barbara Maierhofer, Adriana Badarau, Zehra C Visram, Lukas Stulik, Eszter Nagy
OBJECTIVES: Staphylococcus aureus produces up to five bi-component leukocidins - LukSF-PV, gamma-hemolysins AB and CB, LukGH (LukAB) and LukED - to evade innate immunity by lysing phagocytic cells. Species specificity of these leukocidins limits the relevance of animal models, therefore we assessed their individual contribution using human neutrophils. METHODS: Human polymorphonuclear leukocytes (PMNs) were activated with stimuli relevant during bacterial infections and sensitivity to recombinant leukocidins was measured in cell-viability assays...
May 2017: Journal of Infection
Carmen Alejandra Sabio Y García, Noemí Yokobori, Juan Ignacio Basile, Luciana Balboa, Alejandra González, Beatriz López, Viviana Ritacco, Silvia de la Barrera, María Del Carmen Sasiain
C5a anaphylatoxin is a component of the complement system involved in the modulation of T-cell polarization. Herein we investigated whether C5a receptors, C5aR and C5L2, modulate the cytokine profiles induced by Mycobacterium tuberculosis (Mtb). We analyzed the impact of both receptors on T helper cell polarization induced by the multidrug resistant outbreak strain named M, which is a poor IFN-γ inducer compared with the laboratory strain H37Rv. To this aim, we first blocked C5aR or C5L2 of peripheral blood monocytes (Mo) from patients with tuberculosis and healthy donors, then we stimulated the Mo either with H37Rv or the M strain, and finally we analyzed cytokine profiles of Mo/macrophages (MΦ) and CD4+ T-cells...
March 2017: Tuberculosis
Ying-Ying Zheng, Xiang Xie, Yi-Tong Ma, Zhen-Yan Fu, Xiang Ma, Yi-Ning Yang, Xiao-Mei Li, Shuo Pan, Dilare Adi, Bang-Dang Chen, Fen Liu
BACKGROUND: C5aR-like receptor 2 (C5L2) has been identified as a receptor for the inflammatory factor Complement 5a (C5a) and acylation-stimulating protein (ASP). ASP binding to C5L2 leading to a net accumulation of TG stores and glucose transporter. The aim of the present study is to evaluate the association of the SNPs of C5L2 gene with coronary artery disease (CAD) in a Chinese population. METHODS: We examined the role of the tagging single nucleotide polymorphisms (SNPs) of C5L2 gene for CAD using a case-control design...
January 31, 2017: Oncotarget
F Chmilewsky, I About, S H Chung
The anaphylatoxin C5a constitutes a powerful fragment generated by complement system activation. Interestingly, this complement active fragment is also an important mediator of tissue regeneration. Recent findings suggest that C5a could be an initial signal orchestrating pulp nerve sprouting beneath carious injury, a critical step in dentin-pulp regeneration. Indeed, the expression and activation of the C5a active receptor (C5aR/CD88) by injured pulp fibroblasts controls the direction of neurite outgrowth toward carious injuries by modulating the secretion of brain-derived neurotrophic factor (BDNF) by pulp fibroblasts...
January 2017: Journal of Dental Research
Anne-Catherine Raby, Chantal S Colmont, Ann Kift-Morgan, Jörg Köhl, Matthias Eberl, Donald Fraser, Nicholas Topley, Mario O Labéta
Peritoneal dialysis (PD) remains limited by dialysis failure due to peritoneal membrane fibrosis driven by inflammation caused by infections or sterile cellular stress. Given the fundamental role of Toll-like receptors (TLRs) and complement in inflammation, we assessed the potential of peritoneal TLR2, TLR4 and C5a receptors, C5aR and C5L2, as therapeutic targets in PD-associated fibrosis. We detected TLR2-, TLR4-, and C5aR-mediated proinflammatory and fibrotic responses to bacteria that were consistent with the expression of these receptors in peritoneal macrophages (TLR2/4, C5aR) and mesothelial cells (TLR2, C5aR)...
February 2017: Journal of the American Society of Nephrology: JASN
Ruobing Wang, Bao Lu, Craig Gerard, Norma P Gerard
LPS-induced lung injury in the mouse is one of the most robust experimental models used for studies of acute lung injury (ALI) and acute respiratory distress syndrome in humans. Prior clinical and experimental studies support an important role for complement activation, particularly production of C5a, in the pathophysiology of human ALI/acute respiratory distress syndrome. In the mouse model, however, the precise role of C5a and its receptors is unclear. C5L2, an enigmatic second receptor for C5a, has been characterized, and results have generated substantial debate regarding its in vivo function...
November 2016: American Journal of Respiratory Cell and Molecular Biology
Soumendra Rana, Amita Rani Sahoo, Bharat Kumar Majhi
The phenomena of allosterism continues to advance the field of drug discovery, by illuminating gainful insights for many key processes, related to the structure-function relationships in proteins and enzymes, including the transmembrane G-protein coupled receptors (GPCRs), both in normal as well as in the disease states. However, allosterism is completely unexplored in the native protein ligands, especially when a small covalent change significantly modulates the pharmacology of the protein ligands toward the signaling axes of the GPCRs...
June 2016: Journal of Biomolecular Structure & Dynamics
Jaco Selle, Yaw Asare, Janine Köhncke, Setareh Alampour-Rajabi, Gansuvd Shagdarsuren, Andreas Klos, Christian Weber, Joachim Jankowski, Erdenechimeg Shagdarsuren
Atherogenic processes and vascular remodelling after arterial injury are controlled and driven by a plethora of factors amongst which the activation of the complement system is pivotal. Recently, we reported a clear correlation between high expressions of the second receptor for complement anaphylatoxin C5a, the C5a receptor-like 2 (C5L2, C5aR2), with high pro-inflammatory cytokine expression in advanced human atherosclerotic plaques. This prompted us to speculate that C5aR2 might have a functional role in atherosclerosis...
October 2015: Thrombosis and Haemostasis
Khalid K Alharbi
OBJECTIVES: To investigate the role of amino acid substitution variants Q192R and C698T in the development of glucose-6-phosphate dehydrogenase (G6PD) deficiency in a Saudi male population. METHODS: This case-control study was carried out in 200 Saudi male individuals: 100 patients with G6PD deficiency, and 100 control subjects collected between July and August 2011 in the Taif region of Saudi Arabia. A total of 2100 male Saudi individuals were screened by a fluorescence spot test, and 100 with G6PD deficiency were selected...
May 2015: Saudi Medical Journal
Gaurav Mehta, Robert I Scheinman, V Michael Holers, Nirmal K Banda
Rheumatoid arthritis (RA) is an inflammatory autoimmune joint disease in which the complement system plays an important role. Of the several components of complement, current evidence points to C5 as the most important inducer of inflammation. Several groups generated Abs or small interfering RNAs (siRNAs) or small molecule inhibitors against C5 and C5aR1 (CD88) that have showed some efficacy in RA in animal models. However, none of these candidate therapeutics has moved from bench to bedside. In this study, we test in collagen Ab-induced arthritis (CAIA) a new therapeutic strategy using a novel anti-C5ab-C5 siRNA conjugate...
June 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Ruonan Xu, Fang Lin, Chunmei Bao, Huihuang Huang, Chengcheng Ji, Siyu Wang, Lei Jin, Lijian Sun, Ke Li, Zheng Zhang, Fu-Sheng Wang
Complement 5a (C5a) has been implicated in the pathogenesis of sepsis by inducing the functional impairment of neutrophils; however, the utility of C5a receptors (C5aRs; C5aR and C5L2) as biomarkers for the management of sepsis is uncertain. This study investigated the dynamic expression of C5aR and C5L2 on neutrophils and their effects on neutrophil function. We found that sepsis patients displayed low expression levels of C5aR and C5L2 on neutrophils compared to healthy and systemic inflammatory response syndrome (SIRS) subjects, and this expression pattern was correlated with disease severity...
January 2016: Cellular & Molecular Immunology
Yingying Fang, Chunsheng Li
No abstract text is available yet for this article.
February 2015: Zhonghua Wei Zhong Bing Ji Jiu Yi Xue
András N Spaan, Manouk Vrieling, Pierre Wallet, Cédric Badiou, Tamara Reyes-Robles, Elizabeth A Ohneck, Yvonne Benito, Carla J C de Haas, Christopher J Day, Michael P Jennings, Gérard Lina, François Vandenesch, Kok P M van Kessel, Victor J Torres, Jos A G van Strijp, Thomas Henry
Evasion of the host phagocyte response by Staphylococcus aureus is crucial to successful infection with the pathogen. γ-haemolysin AB and CB (HlgAB, HlgCB) are bicomponent pore-forming toxins present in almost all human S. aureus isolates. Cellular tropism and contribution of the toxins to S. aureus pathophysiology are poorly understood. Here we identify the chemokine receptors CXCR1, CXCR2 and CCR2 as targets for HlgAB, and the complement receptors C5aR and C5L2 as targets for HlgCB. The receptor expression patterns allow the toxins to efficiently and differentially target phagocytic cells...
November 11, 2014: Nature Communications
Owen A Hawksworth, Liam G Coulthard, Stephen M Taylor, Ernst J Wolvetang, Trent M Woodruff
The complement activation product, C5a, is a pivotal member of the innate immune response; however, a diverse number of nonimmune functions are now being ascribed to C5a signaling, including roles during embryonic development. Here, we identify the expression of the C5a precursor protein, C5, as well as the C5a receptors, C5aR and C5L2, in both human embryonic stem cells and human-induced pluripotent stem cells. We show that administration of a physiologically relevant dose of purified human C5a (1 nM) stimulates activation of ERK1/2 and AKT signaling pathways, and is able to promote maintenance of the pluripotent state in the absence of FGF2...
December 2014: Stem Cells
GuiPeng An, GuoRui Ren, FengShuang An, Cheng Zhang
Complement component 5a (C5a) is a 74 amino acid glycoprotein and an important proinflammatory mediator that is cleaved enzymatically from its precursor, C5, on activation of the complement cascade. C5a is quickly metabolised by carboxypeptidases, forming the less-potent C5a desArg. C5a and C5a desArg interact with their receptors (C5aR and C5L2), which results in a number of effects which are essential to the immune response. C5a has a broad range of biological effects throughout the human body because the widespread expression of C5a receptors throughout the human organs enables C5a and C5a desArg to elicit a broad range of biological effects...
August 2014: Science China. Life Sciences
Reza Rezvani, Abhishek Gupta, Jessica Smith, Pegah Poursharifi, Picard Marceau, Louis Pérusse, Claude Bouchard, André Tchernof, Katherine Cianflone
OBJECTIVE: Sex steroid hormones play an important regulatory role in fat metabolism and obesity. We hypothesized involvement of interactions between ovarian hormones with acylation stimulating protein (ASP). DESIGN, PATIENTS AND MEASUREMENTS: In 392 women with wide age (18-69 years) and body size (BMI: 17 to 90 kg/m(2) ) ranges, fasting plasma levels of ASP, ovarian hormones, glucose, adiponectin and lipids/apolipoproteins were assessed, along with determination of metabolic syndrome (MS) features...
November 2014: Clinical Endocrinology
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