CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex

PLoS Pathog. 2012;8(4):e1002597. doi: 10.1371/journal.ppat.1002597. Epub 2012 Apr 5.

Abstract

LPS-activated neutrophils secrete IL-1β by activation of TLR-4. Based on studies in macrophages, it is likely that ROS and lysosomal destabilization regulated by Syk activation may also be involved. Since neutrophils have abundant expression of the ITIM-containing co-receptor CEACAM1 and Gram-negative bacteria such as Neisseria utilize CEACAM1 as a receptor that inhibits inflammation, we hypothesized that the overall production of IL-1β in LPS treated neutrophils may be negatively regulated by CEACAM1. We found that LPS treated neutrophils induced phosphorylation of Syk resulting in the formation of a complex including TLR4, p-Syk, and p-CEACAM1, which in turn, recruited the inhibitory phosphatase SHP-1. LPS treatment leads to ROS production, lysosomal damage, caspase-1 activation and IL-1β secretion in neutrophils. The absence of this regulation in Ceacam1⁻/⁻ neutrophils led to hyper production of IL-1β in response to LPS. The hyper production of IL-1β was abrogated by in vivo reconstitution of wild type but not ITIM-mutated CEACAM1 bone marrow stem cells. Blocking Syk activation by kinase inhibitors or RNAi reduced Syk phosphorylation, lysosomal destabilization, ROS production, and caspase-1 activation in Ceacam1⁻/⁻ neutrophils. We conclude that LPS treatment of neutrophils triggers formation of a complex of TLR4 with pSyk and pCEACAM1, which upon recruitment of SHP-1 to the ITIMs of pCEACAM1, inhibits IL-1β production by the inflammasome. Thus, CEACAM1 fine-tunes IL-1β production in LPS treated neutrophils, explaining why the additional utilization of CEACAM1 as a pathogen receptor would further inhibit inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoembryonic Antigen / genetics
  • Carcinoembryonic Antigen / immunology
  • Carcinoembryonic Antigen / metabolism*
  • Caspase 1 / genetics
  • Caspase 1 / immunology
  • Caspase 1 / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Inflammasomes / genetics
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interleukin-1beta / biosynthesis*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Lysosomes / genetics
  • Lysosomes / immunology
  • Lysosomes / metabolism
  • Lysosomes / pathology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / immunology
  • Multiprotein Complexes / metabolism*
  • Neisseria / immunology
  • Neisseria / metabolism
  • Neisseriaceae Infections / genetics
  • Neisseriaceae Infections / immunology
  • Neisseriaceae Infections / metabolism
  • Neisseriaceae Infections / pathology
  • Neutrophil Activation / drug effects*
  • Neutrophil Activation / genetics
  • Neutrophil Activation / immunology
  • Neutrophils / immunology
  • Neutrophils / metabolism*
  • Neutrophils / pathology
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Phosphorylation / immunology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / immunology
  • Protein-Tyrosine Kinases / metabolism*
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • Syk Kinase
  • Toll-Like Receptor 4 / agonists
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Carcinoembryonic Antigen
  • Ceacam1 protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Multiprotein Complexes
  • Reactive Oxygen Species
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse
  • Caspase 1