title: Loss of Siglec-14 reduces the risk of chronic obstructive pulmonary disease exacerbation.
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.
authors.affiliation: Systems Glycobiology Research Group, and RIKEN-Max Planck Joint Research Center, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. angata@riken.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Angata
authors.forename: Takeo
authors.initials: T
authors.lastname: Ishii
authors.forename: Takashi
authors.initials: T
authors.lastname: Motegi
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Oka
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Taylor
authors.forename: Paula Campos
authors.initials: PC
authors.lastname: Soto
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Chang
authors.forename: Ismael
authors.initials: I
authors.lastname: Secundino
authors.forename: Cong-Xiao
authors.initials: CX
authors.lastname: Gao
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Ohtsubo
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kitazume
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Gemma
authors.forename: Kozui
authors.initials: K
authors.lastname: Kida
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000235:genetics*; D037102:Lectins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D011485:Protein Binding; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D037102:Lectins; D011956:Receptors, Cell Surface; C514213:SIGLEC14 protein, human