title: Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production.
abstract: Sepsis is one of the leading causes of death worldwide. Although the prevailing theory for the sepsis syndrome is a condition of uncontrolled inflammation in response to infection, sepsis is increasingly being recognized as an immunosuppressive state known as endotoxin tolerance. We found sialylation of cell surface was significantly increased on LPS-induced tolerant cells; knockdown of Neu1 in macrophage cell line RAW 264.7 cells resulted in enhanced LPS-induced tolerance, whereas overexpression of Neu1 or treatment with sialidase abrogated LPS-induced tolerance, as defined by measuring TNF-α levels in the culture supernatants. We also found that the expression of Siglec-1 (a member of sialic acid-binding Ig (I)-like lectin family members, the predominant sialic acid-binding proteins on cell surface) was specifically up-regulated in endotoxin tolerant cells and the induction of Siglec-1 suppresses the innate immune response by promoting TGF-β1 production. The enhanced TGF-β1 production by Siglec-1 was significantly attenuated by spleen tyrosine kinase (Syk) inhibitor. Knockdown of siglec-1 in RAW 264.7 cells resulted in inhibiting the production of TGF-β1 by ubiquitin-dependent degradation of Syk. Mechanistically, Siglec-1 associates with adaptor protein DNAX-activation protein of 12 kDa (DAP12) and transduces a signal to Syk to control the production of TGF-β1 in endotoxin tolerance. Thus, Siglec-1 plays an important role in the development of endotoxin tolerance and targeted manipulation of this process could lead to a new therapeutic opportunity for patients with sepsis.
authors.affiliation: From the Children's Foundation Research Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38103.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Children's Foundation Research Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38103.
authors.forename: Chao
authors.initials: C
authors.lastname: Lan
authors.affiliation: From the Children's Foundation Research Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38103.
authors.forename: Dongren
authors.initials: D
authors.lastname: Ren
authors.affiliation: From the Children's Foundation Research Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38103 Gchen14@uthsc.edu.
authors.forename: Guo-Yun
authors.initials: GY
authors.lastname: Chen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004361:Drug Tolerance; D006031:Glycosylation / Q000187:drug effects; D007108:Immune Tolerance; D007113:Immunity, Innate / Q000187:drug effects*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000235:genetics / Q000378:metabolism*; D000072377:Syk Kinase / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D063267:Sialic Acid Binding Ig-like Lectin 1; D053773:Transforming Growth Factor beta1; D000072377:Syk Kinase; C110128:Neu1 protein, mouse; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid
keywords: endotoxin; immunosuppression; neuraminidase; sepsis; sialylation; siglec-1; tolerance