Neutrophils discriminate live from dead bacteria by integrating signals initiated by Fprs and TLRs. (3rd February 2022)

• Record Type: Journal Article
• Authors: Lentini, Germana; De Gaetano, Giuseppe Valerio; Famà, Agata; Galbo, Roberta; Coppolino, Francesco; Mancuso, Giuseppe; Teti, Giuseppe; Beninati, Concetta
• Is Part Of: EMBO journal. Volume 41:Number 5(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-02-03
• Subjects: formylated peptide receptors -- innate immunity -- live/dead discrimination -- neutrophils -- toll‐like receptors; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021109386
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. SYNOPSIS: The presence of viable bacteria is signaled in neutrophils by the simultaneous stimulation of formylated peptide receptor 1 (Fpr1), Fpr2 and toll like receptors. This leads to high‐level production of Cxcl2 and ROS, and to maximal cell activation. Neutrophils produce much higher levels of the Cxcl2 chemokine in response to live bacteria, compared with killed bacteria or isolated bacterial components. High‐level Cxcl2 production is recapitulated by the simultaneous stimulation with agonists for toll‐like receptors, formylated peptide receptor 1 and formylated peptide receptor 2. These stimulation pathways converge at the level of the p38 MAP kinase, leading to activation of the AP‐1 transcription factor and to Cxcl2 induction. Abstract : Live bacteria concomitantly activate Fpr1, Frp2 and Toll‐like receptors to induce p38 MAP kinase signalling, leading to higher levels of the Cxcl2 chemokine and ROS.