Abstract
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. COPD exacerbation, or episodic worsening of symptoms, often results in hospitalization and increased mortality rates. Airway infections by new bacterial strains, such as nontypeable Haemophilus influenzae (NTHi), are a major cause of COPD exacerbation. NTHi express lipooligosaccharides that contain sialic acids, and may interact with Siglec-14, a sialic acid recognition protein on myeloid cells that serves as an activating signal transduction receptor. A null allele polymorphism in SIGLEC14 may attenuate the inflammatory responses to NTHi by eliminating Siglec-14 expression. We asked if the loss of Siglec-14 attenuates the inflammatory response by myeloid cells against NTHi, and if the SIGLEC14-null polymorphism has any effect on COPD exacerbation. We found that NTHi interacts with Siglec-14 to enhance proinflammatory cytokine production in a tissue culture model. Inhibitors of the Syk tyrosine kinase suppress this response. Loss of Siglec-14, due to SIGLEC14-null allele homozygosity, is associated with a reduced risk of COPD exacerbation in a Japanese patient population. Taken together, Siglec-14 and its downstream signaling pathway facilitate the “infection–inflammation–exacerbation” axis of COPD disease progression, and may represent promising targets for therapeutic intervention.
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Acknowledgments
We thank Leela Davies, Xiaoxia Wang and Mina Fujishiro for experimental help, Andrea Verhagen and Sandra Diaz for general laboratory help, and Syed Raza Ali for general discussion. We also thank Dr. Michael A. Apicella (University of Iowa) for the generous gift of NTHi strain 2019. This work was supported by Global COE program “Frontier Biomedical Science Underlying Organelle Network” from the Ministry of Education, Culture, Sports, Science and Technology of Japan to Osaka University (to T.A. and N.T.); the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), Japan (to K.K. and N.T.); and the National Institutes of Health/National Heart, Lung and Blood Institute (NIH/NHLBI) Programs of Excellence in Glycosciences (P01HL107150 to A.V. and V.N.).
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T. Angata and T. Ishii contributed equally to this work.
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Angata, T., Ishii, T., Motegi, T. et al. Loss of Siglec-14 reduces the risk of chronic obstructive pulmonary disease exacerbation. Cell. Mol. Life Sci. 70, 3199–3210 (2013). https://doi.org/10.1007/s00018-013-1311-7
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DOI: https://doi.org/10.1007/s00018-013-1311-7