Bcl10 synergistically links CEACAM3 and TLR-dependent inflammatory signalling

Cell Microbiol. 2018 Jan;20(1). doi: 10.1111/cmi.12788. Epub 2017 Oct 9.

Abstract

The neutrophil-specific innate immune receptor CEACAM3 functions as a decoy to capture Gram-negative pathogens, such as Neisseria gonorrhoeae, that exploit CEACAM family members to adhere to the epithelium. Bacterial binding to CEACAM3 results in their efficient engulfment and triggers activation of an nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent inflammatory response by human neutrophils. Herein, we report that CEACAM3 cross-linking is not sufficient for induction of cytokine production and show that the inflammatory response induced by Neisseria gonorrhoeae infection is elicited by an integration of signals from CEACAM3 and toll-like receptors. Using neutrophils from a human CEACAM-expressing mouse line (CEABAC), we use a genetic approach to reveal a molecular bifurcation of the CEACAM3-mediated antimicrobial and inflammatory responses. Ex vivo experiments with CEABAC-Rac2-/- , CEABAC-Bcl10-/- , and CEABAC-Malt1-/- neutrophils indicate that these effectors are not necessary for gonococcal engulfment, yet all 3 effectors contribute to CEACAM3-mediated cytokine production. Interestingly, although Bcl10 and Malt1 are often inextricably linked, Bcl10 enabled synergy between toll-like receptor 4 and CEACAM3, whereas Malt1 did not. Together, these findings reveal an integration of the specific innate immune receptor CEACAM3 into the network of more conventional pattern recognition receptors, providing a mechanism by which the innate immune system can unleash its response to a relentless pathogen.

Keywords: Bcl10; CEACAM3; Malt1; Neisseria gonorrhoeae; TLR4; neutrophil.

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • B-Cell CLL-Lymphoma 10 Protein / genetics*
  • B-Cell CLL-Lymphoma 10 Protein / immunology
  • Carcinoembryonic Antigen / immunology*
  • Cell Adhesion Molecules / immunology
  • Cells, Cultured
  • GPI-Linked Proteins / immunology
  • Gonorrhea / immunology*
  • Gonorrhea / microbiology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / genetics*
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / immunology
  • Neisseria gonorrhoeae / immunology*
  • Neutrophils / immunology*
  • Toll-Like Receptor 4 / immunology*
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / immunology

Substances

  • Antigens, CD
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CEACAM3 protein, human
  • CEACAM5 protein, human
  • CEACAM6 protein, human
  • CEACAM7 protein, human
  • Carcinoembryonic Antigen
  • Cell Adhesion Molecules
  • GPI-Linked Proteins
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • rac2 GTP-binding protein
  • rac GTP-Binding Proteins