ATF3 is a novel regulator of mouse neutrophil migration
ATF3 is a novel regulator of mouse neutrophil migration
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DOI：
10.1182/blood-2013-06-510909
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发表时间：
2014-03-27
期刊：
影响因子：
20.3
通讯作者：
Karp, Christopher L.
中科院分区：
文献类型：
--
作者：
Boespflug, Nicholas D.;Kumar, Sachin;Karp, Christopher L.
转录激活因子3（ATF 3）基因的表达由Toll样受体（TLR）信号传导诱导。反过来，ATF 3蛋白抑制各种TLR驱动的促炎基因的表达。鉴于其在多种先天性免疫应答中的反调节作用，我们确定了ATF 3对小鼠嗜酸性气道炎症的影响。ATF 3缺失与脂多糖（LPS）驱动的气道上皮细胞产生CXCL 1相关，但与CXCL 2无关，这一发现与仅在Cxcl 1启动子中鉴定的共识ATF 3结合位点一致。出乎意料的是，ATF 3缺陷小鼠在LPS攻击后没有表现出气道嗜酸性粒细胞增多。骨髓嵌合体显示ATF 3（-/-）中性粒细胞募集到野生型肺中的特异性减少。在体外，ATF 3（-/-）中性粒细胞表现出严重的趋化缺陷。全局基因表达分析鉴定了ATF 3（-/-）中性粒细胞中的Tiam 2表达消融。TIAM 2通过激活Rac 1介导的粘着斑解体来调节细胞运动。值得注意的是，ATF 3（-/-）和ATF 3-充足的TIAM 2敲低中性粒细胞（均缺乏TIAM 2）表现出局灶性复合物面积增加，沿着过度的CD 11 b介导的F-肌动蛋白聚合。总之，我们的数据描述了ATF 3介导的调节嗜中性粒细胞反应的二分法作用：抑制中性粒细胞趋化因子的产生，但促进中性粒细胞趋化性。
Expression of the activating transcription factor 3 (ATF3) gene is induced by Toll-like receptor (TLR) signaling. In turn, ATF3 protein inhibits the expression of various TLR-driven proinflammatory genes. Given its counter-regulatory role in diverse innate immune responses, we defined the effects of ATF3 on neutrophilic airway inflammation in mice. ATF3 deletion was associated with increased lipopolysaccharide (LPS)-driven airway epithelia production of CXCL1, but not CXCL2, findings concordant with a consensus ATF3-binding site identified solely in the Cxcl1 promoter. Unexpectedly, ATF3-deficient mice did not exhibit increased airway neutrophilia after LPS challenge. Bone marrow chimeras revealed a specific reduction in ATF3(-/-) neutrophil recruitment to wild-type lungs. In vitro, ATF3(-/-) neutrophils exhibited a profound chemotaxis defect. Global gene expression analysis identified ablated Tiam2 expression in ATF3(-/-) neutrophils. TIAM2 regulates cellular motility by activating Rac1-mediated focal adhesion disassembly. Notably, ATF3(-/-) and ATF3-sufficient TIAM2 knockdown neutrophils, both lacking TIAM2, exhibited increased focal complex area, along with excessive CD11b-mediated F-actin polymerization. Together, our data describe a dichotomous role for ATF3-mediated regulation of neutrophilic responses: inhibition of neutrophil chemokine production but promotion of neutrophil chemotaxis.