title: Siglec-E is up-regulated and phosphorylated following lipopolysaccharide stimulation in order to limit TLR-driven cytokine production.
abstract: Although production of cytokines by TLR is essential for viral and bacterial clearance, overproduction can be detrimental, thus controlling these responses is essential. CD33-related sialic acid binding Ig-like lectin receptors (Siglecs) have been implicated in the control of leukocyte responses. In this study, we report that murine Siglec-E is induced by TLRs in a MyD88-specific manner, is tyrosine phosphorylated following LPS stimulation, and negatively regulates TLR responses. Specifically, we demonstrate the Siglec-E expression inhibits TLR-induced NF-kappaB and more importantly, the induction of the antiviral cytokines IFN-beta and RANTES. Siglec-E mediates its inhibitory effects on TIR domain containing adaptor inducing IFN-beta (TRIF)-dependent cytokine production via recruitment of the tyrosine [corrected] phosphatase SHP2 and subsequent inhibition of TBK1 activity as evidenced by enhanced TBK1 phosphorylation in cells following knockdown of Siglec-E expression. Taken together, our results demonstrate a novel role for Siglec-E in controlling the antiviral response to TLRs and thus helping to maintain a healthy cytokine balance following infection.
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Caroline R
authors.initials: CR
authors.lastname: Boyd
authors.forename: Selinda J
authors.initials: SJ
authors.lastname: Orr
authors.forename: Shaun
authors.initials: S
authors.lastname: Spence
authors.forename: James F
authors.initials: JF
authors.lastname: Burrows
authors.forename: Joanne
authors.initials: J
authors.lastname: Elliott
authors.forename: Helen P
authors.initials: HP
authors.lastname: Carroll
authors.forename: Kiva
authors.initials: K
authors.lastname: Brennan
authors.forename: Joan
authors.initials: J
authors.lastname: Ní Gabhann
authors.forename: Wilson A
authors.initials: WA
authors.lastname: Coulter
authors.forename: Claire
authors.initials: C
authors.lastname: Jones
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crocker
authors.forename: James A
authors.initials: JA
authors.lastname: Johnston
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Jefferies
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D002461:Cell Line, Transformed; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C422908:Siglece protein, mouse; C476286:Ticam1 protein, mouse; C516725:Ptpn11 protein, mouse