Journal
EMBO JOURNAL
Volume 41, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/embj.2021109386
Keywords
formylated peptide receptors; innate immunity; live; dead discrimination; neutrophils; toll-like receptors
Categories
Funding
- PRIN 2017, research Projects of National Relevance [2017M8R7N9]
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The mechanisms of neutrophil response to live and dead organisms are unknown. It has been discovered that neutrophils produce significantly higher levels of the Cxcl2 chemokine in response to live bacteria compared to killed bacteria or isolated bacterial components. This response requires three signals, with two of them being provided by signal peptides released by live bacteria.
The mechanisms whereby neutrophils respond differentially to live and dead organisms are unknown. We show here that neutrophils produce 5- to 30-fold higher levels of the Cxcl2 chemokine in response to live bacteria, compared with killed bacteria or isolated bacterial components, despite producing similar levels of Cxcl1 or pro-inflammatory cytokines. Secretion of high levels of Cxcl2, which potently activates neutrophils by an autocrine mechanism, requires three signals. The first two signals are provided by two different sets of signal peptides released by live bacteria, which selectively activate formylated peptide receptor 1 (Fpr1) and Fpr2, respectively. Signal 3 originates from Toll-like receptor activation by microbial components present in both live and killed bacteria. Mechanistically, these signaling pathways converge at the level of the p38 MAP kinase, leading to activation of the AP-1 transcription factor and to Cxcl2 induction. Collectively, our data demonstrate that the simultaneous presence of agonists for Fpr1, Fpr2, and Toll-like receptors represents a unique signature associated with viable bacteria, which is sensed by neutrophils and induces Cxcl2-dependent autocrine cell activation.
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