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Khoyratty, Tariq E.; Ai, Zhichao; Ballesteros, Ivan; Eames, Hayley L.; Mathie, Sara; Martin-Salamanca, Sandra; Wang, Lihui; Hemmings, Ashleigh; Willemsen, Nicola; Werz, Valentin von; Zehrer, Annette; Walzog, Barbara; Grinsven, Erinke van; Hidalgo, Andres and Udalova, Irina A. (2021): Distinct transcription factor networks control neutrophil-driven inflammation. In: Nature Immunology, Vol. 22, No. 9: 1093-

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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. Neutrophils demonstrate highly dynamic functional and transcriptional changes depending on their tissue environment. Udalova and colleagues use an inflammation model to examine neutrophils and find that the transcription factors RUNX1 and KLF6 control maturation;RELB, IRF5 and JUNB drive effector responses;and RFX2 and RELB promote survival.

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