Dectin-2 recognises mannosylated O-antigens of human opportunistic pathogens and augments lipopolysaccharide activation of myeloid cells

Wittmann, Alexandra, Lamprinaki, Dimitra, Bowles, Kristian M. ORCID: https://orcid.org/0000-0003-1334-4526, Katzenellenbogen, Ewa, Knirel, Yuriy A., Whitfield, Chris, Nishimura, Takashi, Matsumoto, Naoki, Yamamoto, Kazuo, Iwakura, Yoichiro, Saijo, Shinobu and Kawasaki, Norihito (2016) Dectin-2 recognises mannosylated O-antigens of human opportunistic pathogens and augments lipopolysaccharide activation of myeloid cells. Journal of Biological Chemistry, 291 (34). pp. 17629-17638. ISSN 0021-9258

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Abstract

Lipopolysaccharide (LPS) consists of a relatively conserved region of lipid A and core-oligosaccharide, and a highly variable region of O-antigen polysaccharide. While lipid A is known to bind to the toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex, the role of the O-antigen remains unclear. Here we report a novel molecular interaction between dendritic cell-associated C-type lectin-2 (Dectin-2) and the mannosylated O-antigen found in a human opportunistic pathogen Hafnia alvei PCM 1223, which has a repeating unit of [-Man-α1,3-Man-α1,2-Man-α1,2-Man-α1,2-Man-α1,3-]. H. alvei LPS induced higher levels of TNFα and IL-10 from mouse bone marrow-derived dendritic cells (BM-DCs), when compared to Salmonella enterica O66 LPS which has a repeat of [-Gal-α1,6-Gal-α1,4-[Glc-β1,3]GalNAc-α1,3-GalNAc-β1,3-]. In a cell-based reporter assay, Dectin-2 was shown to recognise H. alvei LPS. This binding was inhibited by mannosidase treatment of H. alvei LPS and by mutations in the carbohydrate-binding domain of Dectin-2, demonstrating that H. alvei LPS is a novel glycan ligand of Dectin-2. The enhanced cytokine production by H. alvei LPS was Dectin-2 dependent, as Dectin-2 knockout BM-DCs failed to do so. This receptor crosstalk between Dectin-2 and TLR4 involved events including spleen tyrosine kinase (Syk) activation and receptor juxtaposition. Furthermore, another mannosylated LPS from Escherichia coli O9a, also bound to Dectin-2 and augmented TLR4 activation of BM-DCs. Taken together, these data indicate that mannosylated O-antigens from several gram-negative bacteria augment TLR4 responses through interaction with Dectin-2.

Item Type:	Article
Additional Information:	© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license.
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Depositing User:	Pure Connector
Date Deposited:	24 Sep 2016 00:07
Last Modified:	21 Oct 2022 06:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/59843
DOI:	10.1074/jbc.M116.741256

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