Neutrophils display distinct gene expression patters depending on their developmental stage, activation state and tissue microenvironment. To determine the transcription factor networks that shape these responses in a mouse model, we integrated transcriptional and chromatin analyses of neutrophils during acute inflammation. We showed active chromatin remodeling at two transition stages: bone marrow–to-blood and blood-to-tissue. Analysis of differentially accessible regions revealed distinct sets of putative transcription factors associated with control of neutrophil inflammatory responses. Using ex vivo and in vivo approaches, we confirmed that RUNX1 and KLF6 modulate neutrophil maturation, whereas RELB, IRF5 and JUNB drive neutrophil effector responses and RFX2 and RELB promote survival. Interfering with neutrophil activation by targeting one of these factors, JUNB, reduced pathological inflammation in a mouse model of myocardial infarction. Therefore, our study represents a blueprint for transcriptional control of neutrophil responses in acute inflammation and opens possibilities for stage-specific therapeutic modulation of neutrophil function in disease.

中性粒细胞根据其发育阶段、激活状态和组织微环境表现出不同的基因表达模式。为了确定在小鼠模型中形成这些反应的转录因子网络，我们整合了急性炎症期间中性粒细胞的转录和染色质分析。我们在两个过渡阶段展示了活跃的染色质重塑：骨髓到血液和血液到组织。对差异可及区域的分析揭示了与中性粒细胞炎症反应控制相关的不同假定转录因子组。使用离体和体内方法，我们证实RUNX1和KLF6调节中性粒细胞成熟，而RELB、IRF5和JUNB驱动中性粒细胞效应反应，而RFX2和RELB促进存活。通过靶向这些因子之一 JUNB 来干扰中性粒细胞活化，可减少心肌梗塞小鼠模型的病理性炎症。因此，我们的研究代表了急性炎症中中性粒细胞反应转录控制的蓝图，并为疾病中中性粒细胞功能的阶段特异性治疗调节提供了可能性。