title: The receptor for urokinase regulates TLR2 mediated inflammatory responses in neutrophils.
abstract: The urokinase-type plasminogen activator receptor (uPAR), a glycosylphosphatidylinositol (GPI) anchored membrane protein, regulates urokinase (uPA) protease activity, chemotaxis, cell-cell interactions, and phagocytosis of apoptotic cells. uPAR expression is increased in cytokine or bacteria activated cell populations, including macrophages and monocytes. However, it is unclear if uPAR has direct involvement in the response of inflammatory cells, such as neutrophils and macrophages, to Toll like receptor (TLR) stimulation. In this study, we found that uPAR is required for optimal neutrophil activation after TLR2, but not TLR4 stimulation. We found that the expression of TNF-α and IL-6 induced by TLR2 engagement in uPAR-/- neutrophils was less than that in uPAR+/+ (WT) neutrophils. Pretreatment of neutrophils with PI-PLC, which cleaves GPI moieties, significantly decreased TLR2 induced expression of TNF-α in WT neutrophils, but demonstrated only marginal effects on TNF-α expression in PAM treated uPAR-/- neutrophils. IκB-α degradation and NF-κB activation were not different in uPAR-/- or WT neutrophils after TLR2 stimulation. However, uPAR is required for optimal p38 MAPK activation after TLR2 engagement. Consistent with the in vitro findings that uPAR modulates TLR2 engagement induced neutrophil activation, we found that pulmonary and systemic inflammation induced by TLR2, but not TLR4 stimulation is reduced in uPAR-/- mice compared to WT counterparts. Therefore, our data suggest that neutrophil associated uPAR could be a potential target for treating acute inflammation, sepsis, and organ injury related to severe bacterial and other microbial infections in which TLR2 engagement plays a major role.
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Gang
authors: G
authors: Liu
authors: Yanping
authors: Y
authors: Yang
authors: Shanzhong
authors: S
authors: Yang
authors: Sami
authors: S
authors: Banerjee
authors: Andressa
authors: A
authors: De Freitas
authors: Arnaud
authors: A
authors: Friggeri
authors: Kasey I
authors: KI
authors: Davis
authors: Edward
authors: E
authors: Abraham
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D054800:Glycosylphosphatidylinositol Diacylglycerol-Lyase / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D055666:Lipopeptides / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D055293:Receptors, Urokinase Plasminogen Activator; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; D054800:Glycosylphosphatidylinositol Diacylglycerol-Lyase