Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling
Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling
复制标题
Runx1负性调节中性粒细胞对Toll样受体信号传导的炎性细胞因子产生
DOI：
10.1182/bloodadvances.2019000785
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发表时间：
2020-03-24
期刊：
影响因子：
7.5
通讯作者：
Speck, Nancy A.
中科院分区：
文献类型：
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作者：
Bellissimo, Dana C.;Chen, Chia-hui;Speck, Nancy A.
RUNX1在髓系和淋巴系恶性肿瘤中经常发生突变。已有研究表明，Toll样受体4(TLR4)通过核因子-kappaB(NF-kappa B)负性调节肺上皮细胞Toll样受体4(TLR4)信号传导。在这里，我们发现RUNX1调节TLR1/2和TLR4信号和中性粒细胞炎性细胞因子的产生。造血特异性RUNX1缺失增加了TLR1/2和TLR4激动剂作用下骨髓中性粒细胞产生的促炎介质，包括肿瘤坏死因子-α(TNF-α)。吸入TLR4配体脂多糖(LPS)后，造血性RUNX1的丢失也导致肺实质的严重损害。然而，中性粒细胞特异性RUNX1丢失的中性粒细胞缺乏泛造血RUNX1丢失引起的炎症表型，这表明TLR4信号失控并不是由于中性粒细胞本身丢失RUNX1所致。相反，单细胞RNA测序表明，这种失调源于中性粒细胞前体。在全血液性RUNX1缺失后，中性粒细胞产生的炎性细胞因子增加与NF-kappa B信号抑制物降解增加相关，而RUNX1缺陷的中性粒细胞表现出TLR4信号通路许多核心成分的广泛转录上调。因此，早期的泛造血RUNX1缺失抑制了维持在终末分化的中性粒细胞中的天然免疫信号转录程序，导致它们的高炎症状态。我们假设中性粒细胞产生的炎性细胞因子可能与遗传性RUNX1突变相关的白血病有关。
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 kappa B (NF-kappa B) 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-alpha (TNF-alpha), 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-kappa B 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 hyperinflammatory state. We hypothesize that inflammatory cytokine production by neutrophils may contribute to leukemia associated with inherited RUNX1 mutations.