Soluble CEACAM8 interacts with CEACAM1 inhibiting TLR2-triggered immune responses

• Published in: PloS one 2014-04, Vol.9 (4), p.e94106-e94106
• Main Authors: Singer, Bernhard B, Opp, Lena, Heinrich, Annina, Schreiber, Frauke, Binding-Liermann, Ramona, Berrocal-Almanza, Luis Carlos, Heyl, Kerstin A, Müller, Mario M, Weimann, Andreas, Zweigner, Janine, Slevogt, Hortense
• Format: Article
• Language: English
• Subjects: AKT protein; Analysis; Animals; Antigens; Antigens, CD - chemistry; Antigens, CD - metabolism; Bacteria; Bacterial infections; Biology and Life Sciences; Bronchi - cytology; Bronchi - immunology; Bronchoalveolar Lavage Fluid; Carcinoembryonic antigen; Care and treatment; CD66 antigen; CEACAM1 protein; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - metabolism; Cell Count; Cell Line; Chemokines; Cytochalasin D - pharmacology; Deoxyribonucleic acid; DNA; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelium; GPI-Linked Proteins - chemistry; GPI-Linked Proteins - metabolism; Granulocytes; Granulocytes - cytology; Granulocytes - drug effects; Health aspects; Hospitals; Hostages; Human behavior; Humans; Hygiene; Immune response; Immune system; Immunoglobulins; Immunology; Immunoreceptor tyrosine-based inhibition motif; Infections; Inflammation; Kinases; Laboratories; Leukocytes (granulocytic); Leukocytes (neutrophilic); Medicine and Health Sciences; Moraxella catarrhalis; Neutrophils; Phosphorylation; Physical Sciences; Protein Binding; Proteins; Rats; Recruitment; Respiratory tract; Respiratory tract diseases; SHP-1 protein; Signal Transduction - drug effects; Solubility; TLR2 protein; TLR9 protein; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 9 - metabolism; Toll-like receptors; Tyrosine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094106

Lower respiratory tract bacterial infections are characterized by neutrophilic inflammation in the airways. The carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 8 is expressed in and released by human granulocytes. Our study demonstrates that human granulocytes release CEACAM8 in response to bacterial DNA in a TLR9-dependent manner. Individuals with a high percentage of bronchial lavage fluid (BALF) granulocytes were more likely to have detectable levels of released CEACAM8 in the BALF than those with a normal granulocyte count. Soluble, recombinant CEACAM8-Fc binds to CEACAM1 expressed on human airway epithelium. Application of CEACAM8-Fc to CEACAM1-positive human pulmonary epithelial cells resulted in reduced TLR2-dependent inflammatory responses. These inhibitory effects were accompanied by tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 and by recruitment of the phosphatase SHP-1, which could negatively regulate Toll-like receptor 2-dependent activation of the phosphatidylinositol 3-OH kinase-Akt kinase pathway. Our results suggest a new mechanism by which granulocytes reduce pro-inflammatory immune responses in human airways via secretion of CEACAM8 in neutrophil-driven bacterial infections.