Ebner Florian, Sedlyarov Vitaly, Tasciyan Saren, Ivin Masa, Kratochvill Franz, Gratz Nina, Kenner Lukas, Villunger Andreas, Sixt Michael, Kovarik Pavel
Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Institute of Science and Technology Austria (IST Austria), Klosterneuburg, Austria.
J Clin Invest. 2017 Jun 1;127(6):2051-2065. doi: 10.1172/JCI80631. Epub 2017 May 15.
Protective responses against pathogens require a rapid mobilization of resting neutrophils and the timely removal of activated ones. Neutrophils are exceptionally short-lived leukocytes, yet it remains unclear whether the lifespan of pathogen-engaged neutrophils is regulated differently from that in the circulating steady-state pool. Here, we have found that under homeostatic conditions, the mRNA-destabilizing protein tristetraprolin (TTP) regulates apoptosis and the numbers of activated infiltrating murine neutrophils but not neutrophil cellularity. Activated TTP-deficient neutrophils exhibited decreased apoptosis and enhanced accumulation at the infection site. In the context of myeloid-specific deletion of Ttp, the potentiation of neutrophil deployment protected mice against lethal soft tissue infection with Streptococcus pyogenes and prevented bacterial dissemination. Neutrophil transcriptome analysis revealed that decreased apoptosis of TTP-deficient neutrophils was specifically associated with elevated expression of myeloid cell leukemia 1 (Mcl1) but not other antiapoptotic B cell leukemia/lymphoma 2 (Bcl2) family members. Higher Mcl1 expression resulted from stabilization of Mcl1 mRNA in the absence of TTP. The low apoptosis rate of infiltrating TTP-deficient neutrophils was comparable to that of transgenic Mcl1-overexpressing neutrophils. Our study demonstrates that posttranscriptional gene regulation by TTP schedules the termination of the antimicrobial engagement of neutrophils. The balancing role of TTP comes at the cost of an increased risk of bacterial infections.
针对病原体的保护性反应需要迅速动员静息的中性粒细胞，并及时清除活化的中性粒细胞。中性粒细胞是寿命极短的白细胞，但病原体接触的中性粒细胞的寿命是否与循环稳态池中的中性粒细胞不同，仍不清楚。在这里，我们发现，在稳态条件下，mRNA去稳定蛋白锌指蛋白36（TTP）调节细胞凋亡和活化的浸润性小鼠中性粒细胞数量，但不调节中性粒细胞细胞数量。活化的TTP缺陷型中性粒细胞凋亡减少，在感染部位的积累增加。在骨髓特异性缺失Ttp的情况下，中性粒细胞部署的增强保护小鼠免受化脓性链球菌致死性软组织感染，并防止细菌扩散。中性粒细胞转录组分析显示，TTP缺陷型中性粒细胞凋亡减少与髓系细胞白血病1（Mcl1）表达升高有关，而与其他抗凋亡B细胞淋巴瘤2（Bcl2）家族成员无关。在没有TTP的情况下，Mcl1 mRNA的稳定导致Mcl1表达升高。浸润性TTP缺陷型中性粒细胞的低凋亡率与转基因Mcl1过表达中性粒细胞的凋亡率相当。我们的研究表明，TTP的转录后基因调控决定了中性粒细胞抗菌作用的终止。TTP的平衡作用是以增加细菌感染风险为代价的。
