title: CEACAM1 negatively regulates IL-1β production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex.
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.
authors.affiliation: City of Hope Irell & Manella Graduate School of Biological Sciences, Duarte, California, United States of America.
authors.forename: Rongze
authors.initials: R
authors.lastname: Lu
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.forename: John E
authors.initials: JE
authors.lastname: Shively
mesh_terms: D000818:Animals; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008247:Lysosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009343:Neisseria / Q000276:immunology / Q000378:metabolism; D016870:Neisseriaceae Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018375:Neutrophil Activation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D000072377:Syk Kinase; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; D020170:Caspase 1