title: Siglec-E promotes β2-integrin-dependent NADPH oxidase activation to suppress neutrophil recruitment to the lung.
abstract: Siglec-E is a sialic acid-binding Ig-like lectin expressed on murine myeloid cells. It has recently been shown to function as a negative regulator of β2-integrin-dependent neutrophil recruitment to the lung following exposure to lipopolysaccharide (LPS). Here, we demonstrate that siglec-E promoted neutrophil production of reactive oxygen species (ROS) following CD11b β2-integrin ligation with fibrinogen in a sialic acid-dependent manner, but it had no effect on ROS triggered by a variety of other stimulants. Siglec-E promotion of ROS was likely mediated via Akt activation, because siglec-E-deficient neutrophils plated on fibrinogen exhibited reduced phosphorylation of Akt, and the Akt inhibitor, MK2206, blocked fibrinogen-induced ROS. In vivo imaging showed that siglec-E also promoted ROS in acutely inflamed lungs following exposure of mice to LPS. Importantly, siglec-E-promoted ROS were required for its inhibitory function, as the NADPH oxidase inhibitor, apocynin, reversed the siglec-E-mediated suppression of neutrophil recruitment and blocked neutrophil ROS production in vitro. Taken together, these results demonstrate that siglec-E functions as an inhibitory receptor of neutrophils via positive regulation of NADPH oxidase activation and ROS production. Our findings have implications for the inhibitory role of siglec-9 on human neutrophils in sepsis and acute lung injury.
authors.affiliation: From the Department of Cell Signalling and Immunology, College of Life Sciences, and.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: McMillan
authors.affiliation: From the Department of Cell Signalling and Immunology, College of Life Sciences, and.
authors.forename: Ritu S
authors.initials: RS
authors.lastname: Sharma
authors.affiliation: From the Department of Cell Signalling and Immunology, College of Life Sciences, and.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Richards
authors.affiliation: Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.
authors.forename: Vikas
authors.initials: V
authors.lastname: Hegde
authors.affiliation: From the Department of Cell Signalling and Immunology, College of Life Sciences, and p.r.crocker@dundee.ac.uk.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crocker
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018821:CD18 Antigens / Q000378:metabolism*; D002465:Cell Movement; D004789:Enzyme Activation; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D018821:CD18 Antigens; D006575:Heterocyclic Compounds, 3-Ring; D008070:Lipopolysaccharides; C548887:MK 2206; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C422908:Siglece protein, mouse; D005340:Fibrinogen; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt
keywords: Lipopolysaccharide (LPS); Lung Injury; NADPH Oxidase; Neutrophil; Reactive Oxygen Species (ROS); Siglec-E