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.
This work was supported by the National Institutes of Health (AI063302, AI095587, AI104914, and AI072429 to G.M.B. and EY011108 and EY026082 to K.G.). J.D. is supported by a Long-Term Fellowship from the Human Frontier Science Program (LT-000081/2013-L). G.M.B. is a John P. Stock Faculty Fellow and the recipient of a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease award.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- C-type lectin receptor
- formylated peptide receptor
- liquid chromatography–tandem mass spectrometry
- leukotriene B4
- reactive oxygen species
- trehalose di-behenate
- wild type.
- Received August 23, 2016.
- Accepted January 24, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.