title: Signal inhibitory receptor on leukocytes-1 (SIRL-1) negatively regulates the oxidative burst in human phagocytes.
abstract: ROS production is an important effector mechanism mediating intracellular killing of microbes by phagocytes. Inappropriate or untimely ROS production can lead to tissue damage, thus tight regulation is essential. We recently characterized signal inhibitory receptor on leukocytes-1 (SIRL-1) as an inhibitory receptor expressed by human phagocytes. Here, we demonstrate that ligation of SIRL-1 dampens Fc receptor-induced ROS production in primary human phagocytes. In accordance, SIRL-1 engagement on these cells impairs the microbicidal activity of neutrophils, without affecting phagocytosis. The inhibition of ROS production may result from reduced ERK activation, since co-ligation of Fc receptors and SIRL-1 on phagocytes inhibited phosphorylation of ERK. Importantly, we demonstrate that microbial and inflammatory stimuli cause rapid downregulation of SIRL-1 expression on the surface of primary neutrophils and monocytes. In accordance, SIRL-1 expression levels on neutrophils in bronchoalveolar lavage fluid from patients with neutrophilic airway inflammation are greatly reduced. We propose that SIRL-1 on phagocytes sets an activation threshold to prevent inappropriate production of oxygen radicals. Upon infection, SIRL-1 expression is downregulated, allowing microbial killing and clearance of the pathogen.
authors: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Tessa A M
authors: TA
authors: Steevels
authors: Kristof
authors: K
authors: van Avondt
authors: Geertje H A
authors: GH
authors: Westerlaken
authors: Femke
authors: F
authors: Stalpers
authors: Jona
authors: J
authors: Walk
authors: Louis
authors: L
authors: Bont
authors: Paul J
authors: PJ
authors: Coffer
authors: Linde
authors: L
authors: Meyaard
mesh_terms: D001990:Bronchiolitis, Viral / Q000276:immunology / Q000473:pathology / Q000821:virology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016022:Case-Control Studies; D015169:Colony Count, Microbial; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D007223:Infant; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D011961:Receptors, Fc / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016897:Respiratory Burst / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology; D012137:Respiratory System / Q000276:immunology; D015398:Signal Transduction; D013212:Staphylococcus epidermidis / Q000254:growth & development / Q000276:immunology
chemical_list: D018796:Immunoconjugates; D017382:Reactive Oxygen Species; D011961:Receptors, Fc; D011971:Receptors, Immunologic; C550469:VSTM1 protein, human