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Bacterial lower respiratory tract infections are characterized by neutrophilic inflammation in human airways. The carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 8 is expressed in and released by human granulocytes and interacts with CEACAM1 expressed on human airway epithelium. Here, we demonstrated that CEACAM8 is released by human granulocytes in response to bacterial DNA in a TLR9-dependent manner, whereas expression of CEACAM8 is regulated in a TLR7/8 dependent manner. Individuals with a high percentage of granulocytes in human bronchial lavage fluid (≥ 15 %) were more likely to have detectable levels of released CEACAM8 in the BALF than those with a no or moderately elevated granulocyte count. Interaction of released CEACAM8 with CEACAM1 expressed on human epithelial cells resulted in reduced TLR2 dependent inflammatory responses. These inhibitory effects were mediated by tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 and by recruitment of the phosphatase SHP-1, which negatively regulated Toll-like receptor 2-dependent activation of the phosphatidylinositol 3-OH kinase-Akt kinase pathway. In conclusion, our results suggest a new mechanism by which granulocytes reduce proinflammatory immune responses in the human airways via secretion of CEACAM8 in neutrophil-driven bacterial infections.
Thus, the released CEACAM8 might serve as granulocytic resolution-associated molecular pattern interacting with CEACAM1 expressed on human bronchial epithelial cells to avoid hyper-inflammation and to prevent tissue damage.