title: Local TNFR1 Signaling Licenses Murine Neutrophils for Increased TLR-Dependent Cytokine and Eicosanoid Production.
abstract: Neutrophils are generally the first immune cells recruited during the development of sterile or microbial inflammation. As these cells express many innate immune receptors with the potential to directly recognize microbial or endogenous signals, we set out to assess whether their functions are locally influenced by the signals present at the onset of inflammation. Using a mouse model of peritonitis, we demonstrate that neutrophils elicited in the presence of C-type lectin receptor ligands have an increased ability to produce cytokines, chemokines, and lipid mediators in response to subsequent TLR stimulation. Importantly, we found that licensing of cytokine production was mediated by paracrine TNF-α-TNFR1 signaling rather than direct ligand sensing, suggesting a form of quorum sensing among neutrophils. Mechanistically, licensing was largely imparted by changes in the posttranscriptional regulation of inflammatory cytokines, whereas production of IL-10 was regulated at the transcriptional level. Altogether, our data suggest that neutrophils rapidly adapt their functions to the local inflammatory milieu. These phenotypic changes may promote rapid neutrophil recruitment in the presence of pathogens but limit inflammation in their absence.
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720; and.
authors.forename: Jacques
authors.initials: J
authors.lastname: Deguine
authors.affiliation: Vision Science Program, School of Optometry, University of California Berkeley, Berkeley, CA 94598.
authors.forename: Jessica
authors.identifier: 0000-0002-7329-2812
authors.initials: J
authors.lastname: Wei
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720; and.
authors.forename: Roman
authors.identifier: 0000-0003-2139-913X
authors.initials: R
authors.lastname: Barbalat
authors.affiliation: Vision Science Program, School of Optometry, University of California Berkeley, Berkeley, CA 94598.
authors.forename: Karsten
authors.initials: K
authors.lastname: Gronert
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720; and barton@berkeley.edu.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Barton
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000096:biosynthesis*; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D010538:Peritonitis / Q000276:immunology; D016133:Polymerase Chain Reaction; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D016207:Cytokines; D015777:Eicosanoids; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D051193:Toll-Like Receptors