Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling

作者：Dana C. Bellissimo, Chia-Hui Chen, Qin Zhu, Sumedha Bagga, Chung-Tsai Lee, Bing He, Gerald B. W. Wertheim, Martha S. Jordan, Kai Tan, George Scott Worthen, D. Gary Gilliland, Nancy A. Speck · 发表于：Blood Advances · 年份：2020 · DOI：10.1182/bloodadvances.2019000785 · 被引用次数：82 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Immune Response and Inflammation、Immune cells in cancer

RUNX1 is frequently mutated in myeloid and lymphoid malignancies. It has been shown to negatively regulate Toll-like receptor 4 (TLR4) signaling through nuclear factor κB (NF-κB) in lung epithelial cells. Here we show that RUNX1 regulates TLR1/2 and TLR4 signaling and inflammatory cytokine production by neutrophils. Hematopoietic-specific RUNX1 loss increased the production of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), by bone marrow neutrophils in response to TLR1/2 and TLR4 agonists. Hematopoietic RUNX1 loss also resulted in profound damage to the lung parenchyma following inhalation of the TLR4 ligand lipopolysaccharide (LPS). However, neutrophils with neutrophil-specific RUNX1 loss lacked the inflammatory phenotype caused by pan-hematopoietic RUNX1 loss, indicating that dysregulated TLR4 signaling is not due to loss of RUNX1 in neutrophils per se. Rather, single-cell RNA sequencing indicates the dysregulation originates in a neutrophil precursor. Enhanced inflammatory cytokine production by neutrophils following pan-hematopoietic RUNX1 loss correlated with increased degradation of the inhibitor of NF-κB signaling, and RUNX1-deficient neutrophils displayed broad transcriptional upregulation of many of the core components of the TLR4 signaling pathway. Hence, early, pan-hematopoietic RUNX1 loss de-represses an innate immune signaling transcriptional program that is maintained in terminally differentiated neutrophils, resulting in their hyperinflam...