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Regulators and Effectors of Arf GTPases in Neutrophils.

Gamara J, Chouinard F, Davis L, Aoudjit F, Bourgoin SG - J Immunol Res (2015)

Bottom Line: In this review, we will focus on the small monomeric GTPases of the Arf family and their guanine exchange factors (GEFs) and GTPase activating proteins (GAPs) as components of signalling cascades regulating PMN responses.GEFs and GAPs are multidomain proteins that control cellular events in time and space through interaction with other proteins and lipids inside the cells.The number of Arf GAPs identified in PMNs is expanding, and dissecting their functions will provide important insights into the role of these proteins in PMN physiology.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases and Immunology, CHU de Quebec Research Center, Quebec, QC, Canada G1V 4G2.

ABSTRACT
Polymorphonuclear neutrophils (PMNs) are key innate immune cells that represent the first line of defence against infection. They are the first leukocytes to migrate from the blood to injured or infected sites. This process involves molecular mechanisms that coordinate cell polarization, delivery of receptors, and activation of integrins at the leading edge of migrating PMNs. These phagocytes actively engulf microorganisms or form neutrophil extracellular traps (NETs) to trap and kill pathogens with bactericidal compounds. Association of the NADPH oxidase complex at the phagosomal membrane for production of reactive oxygen species (ROS) and delivery of proteolytic enzymes into the phagosome initiate pathogen killing and removal. G protein-dependent signalling pathways tightly control PMN functions. In this review, we will focus on the small monomeric GTPases of the Arf family and their guanine exchange factors (GEFs) and GTPase activating proteins (GAPs) as components of signalling cascades regulating PMN responses. GEFs and GAPs are multidomain proteins that control cellular events in time and space through interaction with other proteins and lipids inside the cells. The number of Arf GAPs identified in PMNs is expanding, and dissecting their functions will provide important insights into the role of these proteins in PMN physiology.

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Related in: MedlinePlus

Main steps in PMN transmigration and regulation of PMN functional responses by Arfs and their regulators. (a) Schematic representation of PMN extravasation in infectious and noninfectious diseases. The first contact with endothelial cells is mediated by engagement of selectins with their counterreceptor P-selectin glycoprotein ligand-1 (PSGL-1) which results in capture and rolling of PMNs. Activation of PMNs by selectins and the different inflammatory signals like chemokines while rolling induces activation of the β2 integrins (LFA-1 and Mac-1) and slow rolling. Binding of activated β2 integrins to their counterreceptors ICAMs on endothelial cells induces PMN arrest due to firm adhesion and Mac-1-dependent crawling. Polarization of PMNs toward the chemoattractant source (i.e., cytoskeletal rearrangement, recruitment of regulators of Arfs, and activation of PI3Kγ, Arf1, and NADPH oxidase at the leading edge) initiates directional sensing and transmigration across the vascular endothelium. PMNs are guided by the gradient of chemoattractant factors and after arriving at the site of infection or tissue injury, the cells initiate phagocytosis or NETosis to kill pathogens and remove cellular debris. PMN granules are schematically represented by colored circles. (b) Signalling pathways downstream of GPCRs, Fcγ receptor IIA (FcγRIIA), and β2 integrins by which Arfs and their regulators are thought to regulate PMN functional responses are presented schematically. Green arrows indicate direct activation either through lipid-protein or through protein-protein interactions, and negative feedback mechanisms are highlighted in red. Where direct interactions have not been established and/or the signalling mechanisms are unclear, lines are dotted. Cross talk between Arf and Rho family GTPases mediated by ARAP3 and the p21 protein- (Cdc42/Rac-) activated kinase 1 (PAK1)/PAK-interacting Exchange Factor alpha (αPIX) signalling complex is also shown.
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Related In: Results  -  Collection


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fig1: Main steps in PMN transmigration and regulation of PMN functional responses by Arfs and their regulators. (a) Schematic representation of PMN extravasation in infectious and noninfectious diseases. The first contact with endothelial cells is mediated by engagement of selectins with their counterreceptor P-selectin glycoprotein ligand-1 (PSGL-1) which results in capture and rolling of PMNs. Activation of PMNs by selectins and the different inflammatory signals like chemokines while rolling induces activation of the β2 integrins (LFA-1 and Mac-1) and slow rolling. Binding of activated β2 integrins to their counterreceptors ICAMs on endothelial cells induces PMN arrest due to firm adhesion and Mac-1-dependent crawling. Polarization of PMNs toward the chemoattractant source (i.e., cytoskeletal rearrangement, recruitment of regulators of Arfs, and activation of PI3Kγ, Arf1, and NADPH oxidase at the leading edge) initiates directional sensing and transmigration across the vascular endothelium. PMNs are guided by the gradient of chemoattractant factors and after arriving at the site of infection or tissue injury, the cells initiate phagocytosis or NETosis to kill pathogens and remove cellular debris. PMN granules are schematically represented by colored circles. (b) Signalling pathways downstream of GPCRs, Fcγ receptor IIA (FcγRIIA), and β2 integrins by which Arfs and their regulators are thought to regulate PMN functional responses are presented schematically. Green arrows indicate direct activation either through lipid-protein or through protein-protein interactions, and negative feedback mechanisms are highlighted in red. Where direct interactions have not been established and/or the signalling mechanisms are unclear, lines are dotted. Cross talk between Arf and Rho family GTPases mediated by ARAP3 and the p21 protein- (Cdc42/Rac-) activated kinase 1 (PAK1)/PAK-interacting Exchange Factor alpha (αPIX) signalling complex is also shown.

Mentions: Rapid recruitment of innate immunity cells such as polymorphonuclear neutrophils (PMNs) is a critical component of pathogen killing and removal during infection. PMNs are generated from hematopoietic stem cells located in the bone marrow. A normal adult is estimated to produce about 100 billion of these PMNs daily. As they differentiate, the cells begin to move toward the venous sinusoids prior to migration across the sinusoidal endothelium to reach the vascular lumen. These terminally differentiated cells have a short life [1] but nevertheless represent the most abundant leukocyte species in the circulation. PMNs are the first leukocytes to migrate from the blood to inflammatory sites [2, 3]. Following their activation by various proinflammatory cytokines such as IL-8, TNFα, or IL-1β secreted by resident macrophages, PMNs start rolling along the vessel wall, followed by firm arrest and transmigration through the inflammatory vascular endothelium [4–6]. Once in the extravascular environment, PMNs interact with extracellular matrix proteins and migrate along a chemotactic gradient to reach the site of injury [7]. At the site of infection, PMNs begin phagocytosis and killing of pathogens through production of toxic reactive oxygen species (ROS), secretion of lysosomal enzymes, and formation of NETs (Figure 1(a)) [2, 8]. Activated PMNs also regulate the innate and the adaptive immune responses by secretion of various cytokines and chemokines, such as IL-1, IL-6, IL-8, TNFα [2, 9–11], and lipid mediators as well [12]. The interaction of PMNs with their environment is an indispensable determinant that tailors their functional responses, including correct timing of events leading to activation. The mechanisms that contribute to the maintenance of PMN homeostasis under normal and inflammatory conditions are tightly regulated through integration of external signals picked up by their transmembrane receptors. These receptors mediate intracellular signalling cascades through activation of two superfamilies of G proteins, the heterotrimeric G proteins, and the RAS superfamily of small monomeric GTPases [13, 14]. Whereas heterotrimeric G proteins directly interact with and are activated following stimulation of so-called G protein-coupled receptors (GPCRs) such as formyl-peptide receptors or CXCR1 chemokine receptor, small GTPases are generally activated by other regulatory proteins downstream of many transmembrane receptors (Figure 1(b)).


Regulators and Effectors of Arf GTPases in Neutrophils.

Gamara J, Chouinard F, Davis L, Aoudjit F, Bourgoin SG - J Immunol Res (2015)

Main steps in PMN transmigration and regulation of PMN functional responses by Arfs and their regulators. (a) Schematic representation of PMN extravasation in infectious and noninfectious diseases. The first contact with endothelial cells is mediated by engagement of selectins with their counterreceptor P-selectin glycoprotein ligand-1 (PSGL-1) which results in capture and rolling of PMNs. Activation of PMNs by selectins and the different inflammatory signals like chemokines while rolling induces activation of the β2 integrins (LFA-1 and Mac-1) and slow rolling. Binding of activated β2 integrins to their counterreceptors ICAMs on endothelial cells induces PMN arrest due to firm adhesion and Mac-1-dependent crawling. Polarization of PMNs toward the chemoattractant source (i.e., cytoskeletal rearrangement, recruitment of regulators of Arfs, and activation of PI3Kγ, Arf1, and NADPH oxidase at the leading edge) initiates directional sensing and transmigration across the vascular endothelium. PMNs are guided by the gradient of chemoattractant factors and after arriving at the site of infection or tissue injury, the cells initiate phagocytosis or NETosis to kill pathogens and remove cellular debris. PMN granules are schematically represented by colored circles. (b) Signalling pathways downstream of GPCRs, Fcγ receptor IIA (FcγRIIA), and β2 integrins by which Arfs and their regulators are thought to regulate PMN functional responses are presented schematically. Green arrows indicate direct activation either through lipid-protein or through protein-protein interactions, and negative feedback mechanisms are highlighted in red. Where direct interactions have not been established and/or the signalling mechanisms are unclear, lines are dotted. Cross talk between Arf and Rho family GTPases mediated by ARAP3 and the p21 protein- (Cdc42/Rac-) activated kinase 1 (PAK1)/PAK-interacting Exchange Factor alpha (αPIX) signalling complex is also shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
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fig1: Main steps in PMN transmigration and regulation of PMN functional responses by Arfs and their regulators. (a) Schematic representation of PMN extravasation in infectious and noninfectious diseases. The first contact with endothelial cells is mediated by engagement of selectins with their counterreceptor P-selectin glycoprotein ligand-1 (PSGL-1) which results in capture and rolling of PMNs. Activation of PMNs by selectins and the different inflammatory signals like chemokines while rolling induces activation of the β2 integrins (LFA-1 and Mac-1) and slow rolling. Binding of activated β2 integrins to their counterreceptors ICAMs on endothelial cells induces PMN arrest due to firm adhesion and Mac-1-dependent crawling. Polarization of PMNs toward the chemoattractant source (i.e., cytoskeletal rearrangement, recruitment of regulators of Arfs, and activation of PI3Kγ, Arf1, and NADPH oxidase at the leading edge) initiates directional sensing and transmigration across the vascular endothelium. PMNs are guided by the gradient of chemoattractant factors and after arriving at the site of infection or tissue injury, the cells initiate phagocytosis or NETosis to kill pathogens and remove cellular debris. PMN granules are schematically represented by colored circles. (b) Signalling pathways downstream of GPCRs, Fcγ receptor IIA (FcγRIIA), and β2 integrins by which Arfs and their regulators are thought to regulate PMN functional responses are presented schematically. Green arrows indicate direct activation either through lipid-protein or through protein-protein interactions, and negative feedback mechanisms are highlighted in red. Where direct interactions have not been established and/or the signalling mechanisms are unclear, lines are dotted. Cross talk between Arf and Rho family GTPases mediated by ARAP3 and the p21 protein- (Cdc42/Rac-) activated kinase 1 (PAK1)/PAK-interacting Exchange Factor alpha (αPIX) signalling complex is also shown.
Mentions: Rapid recruitment of innate immunity cells such as polymorphonuclear neutrophils (PMNs) is a critical component of pathogen killing and removal during infection. PMNs are generated from hematopoietic stem cells located in the bone marrow. A normal adult is estimated to produce about 100 billion of these PMNs daily. As they differentiate, the cells begin to move toward the venous sinusoids prior to migration across the sinusoidal endothelium to reach the vascular lumen. These terminally differentiated cells have a short life [1] but nevertheless represent the most abundant leukocyte species in the circulation. PMNs are the first leukocytes to migrate from the blood to inflammatory sites [2, 3]. Following their activation by various proinflammatory cytokines such as IL-8, TNFα, or IL-1β secreted by resident macrophages, PMNs start rolling along the vessel wall, followed by firm arrest and transmigration through the inflammatory vascular endothelium [4–6]. Once in the extravascular environment, PMNs interact with extracellular matrix proteins and migrate along a chemotactic gradient to reach the site of injury [7]. At the site of infection, PMNs begin phagocytosis and killing of pathogens through production of toxic reactive oxygen species (ROS), secretion of lysosomal enzymes, and formation of NETs (Figure 1(a)) [2, 8]. Activated PMNs also regulate the innate and the adaptive immune responses by secretion of various cytokines and chemokines, such as IL-1, IL-6, IL-8, TNFα [2, 9–11], and lipid mediators as well [12]. The interaction of PMNs with their environment is an indispensable determinant that tailors their functional responses, including correct timing of events leading to activation. The mechanisms that contribute to the maintenance of PMN homeostasis under normal and inflammatory conditions are tightly regulated through integration of external signals picked up by their transmembrane receptors. These receptors mediate intracellular signalling cascades through activation of two superfamilies of G proteins, the heterotrimeric G proteins, and the RAS superfamily of small monomeric GTPases [13, 14]. Whereas heterotrimeric G proteins directly interact with and are activated following stimulation of so-called G protein-coupled receptors (GPCRs) such as formyl-peptide receptors or CXCR1 chemokine receptor, small GTPases are generally activated by other regulatory proteins downstream of many transmembrane receptors (Figure 1(b)).

Bottom Line: In this review, we will focus on the small monomeric GTPases of the Arf family and their guanine exchange factors (GEFs) and GTPase activating proteins (GAPs) as components of signalling cascades regulating PMN responses.GEFs and GAPs are multidomain proteins that control cellular events in time and space through interaction with other proteins and lipids inside the cells.The number of Arf GAPs identified in PMNs is expanding, and dissecting their functions will provide important insights into the role of these proteins in PMN physiology.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases and Immunology, CHU de Quebec Research Center, Quebec, QC, Canada G1V 4G2.

ABSTRACT
Polymorphonuclear neutrophils (PMNs) are key innate immune cells that represent the first line of defence against infection. They are the first leukocytes to migrate from the blood to injured or infected sites. This process involves molecular mechanisms that coordinate cell polarization, delivery of receptors, and activation of integrins at the leading edge of migrating PMNs. These phagocytes actively engulf microorganisms or form neutrophil extracellular traps (NETs) to trap and kill pathogens with bactericidal compounds. Association of the NADPH oxidase complex at the phagosomal membrane for production of reactive oxygen species (ROS) and delivery of proteolytic enzymes into the phagosome initiate pathogen killing and removal. G protein-dependent signalling pathways tightly control PMN functions. In this review, we will focus on the small monomeric GTPases of the Arf family and their guanine exchange factors (GEFs) and GTPase activating proteins (GAPs) as components of signalling cascades regulating PMN responses. GEFs and GAPs are multidomain proteins that control cellular events in time and space through interaction with other proteins and lipids inside the cells. The number of Arf GAPs identified in PMNs is expanding, and dissecting their functions will provide important insights into the role of these proteins in PMN physiology.

Show MeSH
Related in: MedlinePlus