Department of Human Pathology, University of Messina, Messina, Italy.
Department of Chemical, Biological and Pharmaceutical Sciences, University of Messina, Messina, Italy.
EMBO J. 2022 Mar 1;41(5):e109386. doi: 10.15252/embj.2021109386. Epub 2022 Feb 3.
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.
中性粒细胞对活的和死的生物体产生不同反应的机制尚不清楚。我们在这里表明，与死亡细菌或分离的细菌成分相比，中性粒细胞对活细菌产生的趋化因子 Cxcl2 的水平要高出 5 到 30 倍，尽管它们产生的趋化因子 Cxcl1 或促炎细胞因子水平相似。高水平的 Cxcl2 分泌通过自分泌机制强烈激活中性粒细胞，需要三个信号。前两个信号由活细菌释放的两套不同的信号肽提供，分别选择性地激活甲酰肽受体 1（Fpr1）和 Fpr2。信号 3 源自 Toll 样受体激活，由活细菌和死细菌中存在的微生物成分引发。从机制上讲，这些信号通路在 p38 MAP 激酶水平上汇聚，导致 AP-1 转录因子的激活和 Cxcl2 的诱导。总的来说，我们的数据表明，Fpr1、Fpr2 和 Toll 样受体激动剂的同时存在代表了与存活细菌相关的独特特征，被中性粒细胞感知并诱导 Cxcl2 依赖性自分泌细胞激活。
