Siglec-7 Mediates Immunomodulation by Colorectal Cancer-Associated Fusobacterium nucleatum ssp. animalis

TY - JOUR

T1 - Siglec-7 Mediates Immunomodulation by Colorectal Cancer-Associated Fusobacterium nucleatum ssp. animalis

AU - Lamprinaki, Dimitra

AU - Garcia-Vello, Pilar

AU - Marchetti, Roberta

AU - Hellmich, Charlotte

AU - McCord, Kelli A.

AU - Bowles, Kristian M.

AU - Macauley, Matthew S.

AU - Silipo, Alba

AU - De Castro, Cristina

AU - Crocker, Paul R.

AU - Juge, Nathalie

N1 - Funding Information: The authors gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); this research was funded by the BBSRC Institute Strategic Programme Gut Microbes and Health BB/R012490/1 Funding Information: The authors gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); this research was funded by the BBSRC Institute Strategic Programme Gut Microbes and Health BB/R012490/1 and its constituent project BBS/E/F/000PR10353 (Theme 1, Determinants of microbe-host responses in the gut across life). DL was supported by the BBSRC Norwich Research Park Biosciences Doctoral Training Partnership grant number BB/M011216/1. PGV acknowledges financial support from the European Commission via the International Training Network Train2Target (721484). AS was supported by PRIN 2017 (2017XZ2ZBK, 2019-2022), RM was supported by the European Research Council (ERC) under the European Union?s Horizon 2020 research and innovation programme, grant agreement number 851356. Work in the PRC lab was supported by Wellcome Trust grant 103744/Z/14/Z. MM acknowledges funding from GlycoNet, NSERC, and a Canada Tier II research chair in Chemical Glycoimmunology. KM acknowledges support through an Alberta Graduate Excellence Scholarship. Publisher Copyright: © Copyright © 2021 Lamprinaki, Garcia-Vello, Marchetti, Hellmich, McCord, Bowles, Macauley, Silipo, De Castro, Crocker and Juge.

PY - 2021/10/1

Y1 - 2021/10/1

N2 - Fusobacterium nucleatum is involved in the development of colorectal cancer (CRC) through innate immune cell modulation. However, the receptors of the interaction between F. nucleatum ssp. and immune cells remain largely undetermined. Here, we showed that F. nucleatum ssp. animalis interacts with Siglecs (sialic acid-binding immunoglobulin-like lectins) expressed on innate immune cells with highest binding to Siglec-7. Binding to Siglec-7 was also observed using F. nucleatum-derived outer membrane vesicles (OMVs) and lipopolysaccharide (LPS). F. nucleatum and its derived OMVs or LPS induced a pro-inflammatory profile in human monocyte-derived dendritic cells (moDCs) and a tumour associated profile in human monocyte-derived macrophages (moMϕs). Siglec-7 silencing in moDCs or CRISPR-cas9 Siglec-7-depletion of U-937 macrophage cells altered F. nucleatum induced cytokine but not marker expression. The molecular interaction between Siglec-7 and the LPS O-antigen purified from F. nucleatum ssp. animalis was further characterised by saturation transfer difference (STD) NMR spectroscopy, revealing novel ligands for Siglec-7. Together, these data support a new role for Siglec-7 in mediating immune modulation by F. nucleatum strains and their OMVs through recognition of LPS on the bacterial cell surface. This opens a new dimension in our understanding of how F. nucleatum promotes CRC progression through the generation of a pro-inflammatory environment and provides a molecular lead for the development of novel cancer therapeutic approaches targeting F. nucleatum-Siglec-7 interaction.

AB - Fusobacterium nucleatum is involved in the development of colorectal cancer (CRC) through innate immune cell modulation. However, the receptors of the interaction between F. nucleatum ssp. and immune cells remain largely undetermined. Here, we showed that F. nucleatum ssp. animalis interacts with Siglecs (sialic acid-binding immunoglobulin-like lectins) expressed on innate immune cells with highest binding to Siglec-7. Binding to Siglec-7 was also observed using F. nucleatum-derived outer membrane vesicles (OMVs) and lipopolysaccharide (LPS). F. nucleatum and its derived OMVs or LPS induced a pro-inflammatory profile in human monocyte-derived dendritic cells (moDCs) and a tumour associated profile in human monocyte-derived macrophages (moMϕs). Siglec-7 silencing in moDCs or CRISPR-cas9 Siglec-7-depletion of U-937 macrophage cells altered F. nucleatum induced cytokine but not marker expression. The molecular interaction between Siglec-7 and the LPS O-antigen purified from F. nucleatum ssp. animalis was further characterised by saturation transfer difference (STD) NMR spectroscopy, revealing novel ligands for Siglec-7. Together, these data support a new role for Siglec-7 in mediating immune modulation by F. nucleatum strains and their OMVs through recognition of LPS on the bacterial cell surface. This opens a new dimension in our understanding of how F. nucleatum promotes CRC progression through the generation of a pro-inflammatory environment and provides a molecular lead for the development of novel cancer therapeutic approaches targeting F. nucleatum-Siglec-7 interaction.

KW - colorectal cancer

KW - Fusobacterium nucleatum

KW - innate immunity

KW - lipopolysaccharide

KW - outer membrane vesicle

KW - Siglec-7

UR - https://www.scopus.com/pages/publications/85117186059

U2 - 10.3389/fimmu.2021.744184

DO - 10.3389/fimmu.2021.744184

M3 - Article

C2 - 34659241

SN - 1664-3224

VL - 12

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 744184

ER -