title: Moraxella catarrhalis induces CEACAM3-Syk-CARD9-dependent activation of human granulocytes.
abstract: The human restricted pathogen Moraxella catarrhalis is an important causal agent for exacerbations in chronic obstructive lung disease in adults. In such patients, increased numbers of granulocytes are present in the airways, which correlate with bacteria-induced exacerbations and severity of the disease. Our study investigated whether the interaction of M. catarrhalis with the human granulocyte-specific carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-3 is linked to NF-κB activation, resulting in chemokine production. Granulocytes from healthy donors and NB4 cells were infected with M. catarrhalis in the presence of different inhibitors, blocking antibodies and siRNA. The supernatants were analysed by enzyme-linked immunosorbent assay for chemokines. NF-κB activation was determined using a luciferase reporter gene assay and chromatin-immunoprecipitation. We found evidence that the specific engagement of CEACAM3 by M. catarrhalis ubiquitous surface protein A1 (UspA1) results in the activation of pro-inflammatory events, such as degranulation of neutrophils, ROS production and chemokine secretion. The interaction of UspA1 with CEACAM3 induced the activation of the NF-κB pathway via Syk and the CARD9 pathway and was dependent on the phosphorylation of the CEACAM3 ITAM-like motif. These findings suggest that the CEACAM3 signalling in neutrophils is able to specifically modulate airway inflammation caused by infection with M. catarrhalis.
authors.affiliation: Septomics Research Center, Jena University Hospital, Jena, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Heinrich
authors.affiliation: Septomics Research Center, Jena University Hospital, Jena, Germany.
authors.forename: K A
authors.initials: KA
authors.lastname: Heyl
authors.affiliation: Septomics Research Center, Jena University Hospital, Jena, Germany.|Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Klaile
authors.affiliation: Septomics Research Center, Jena University Hospital, Jena, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Müller
authors.affiliation: Septomics Research Center, Jena University Hospital, Jena, Germany.
authors.forename: T E
authors.initials: TE
authors.lastname: Klassert
authors.affiliation: Biofilmcenter, German Heart Institute Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Wiessner
authors.affiliation: Septomics Research Center, Jena University Hospital, Jena, Germany.|Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Institute for Microbiology and Hygiene, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: R R
authors.initials: RR
authors.lastname: Schumann
authors.affiliation: Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Seifert
authors.affiliation: Clinical Microbiology, Department of Translational Medicine, Lund University, Malmö, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Riesbeck
authors.affiliation: Biofilmcenter, German Heart Institute Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Moter
authors.affiliation: Institute of Anatomy, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: B B
authors.initials: BB
authors.lastname: Singer
authors.affiliation: Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bachmann
authors.affiliation: Septomics Research Center, Jena University Hospital, Jena, Germany. hortense.slevogt@med.uni-jena.de.
authors.forename: H
authors.initials: H
authors.lastname: Slevogt
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D015550:Cell Degranulation; D018925:Chemokines / Q000378:metabolism; D006098:Granulocytes / Q000382:microbiology / Q000502:physiology*; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D001936:Moraxella catarrhalis / Q000502:physiology*; D045828:Moraxellaceae Infections / Q000382:microbiology*; D016897:Respiratory Burst; D015398:Signal Transduction; D000072377:Syk Kinase / Q000378:metabolism*
chemical_list: D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; C075729:CEACAM3 protein, human; D002272:Carcinoembryonic Antigen; D018925:Chemokines; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: CARD9; CEACAM3; COPD; Moraxella catarrhalis; Syk; granulocyte; immunoreceptor tyrosine-based activation motif (ITAM)