Zhang Songen, Zhang Su, Garcia-Vaz Eliana, Herwald Heiko, Gomez Maria F, Thorlacius Henrik
Sections for *Surgery and Vascular Excitation-Transcription Coupling, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; and Department of Clinical Sciences Lund, Section for Clinical and Experimental Infection Medicine, Lund University, Sweden.
Sections for *Surgery and Vascular Excitation-Transcription Coupling, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; and Department of Clinical Sciences Lund, Section for Clinical and Experimental Infection Medicine, Lund University, Sweden
J Leukoc Biol. 2015 Jun;97(6):1003-10. doi: 10.1189/jlb.3HI0214-123RR. Epub 2015 Jan 12.
Streptococcus pyogenes of the M1 serotype can cause STSS, which is associated with significant morbidity and mortality. The purpose of the present study was to examine the role of NFAT signaling in M1 protein-induced lung injury. NFAT-luc mice were treated with the NFAT inhibitor A-285222 before administration of the M1 protein. Neutrophil infiltration, edema, and CXC chemokines were quantified in the lung, 4 h after challenge with the M1 protein. Flow cytometry was used to determine Mac-1 expression. Challenge with the M1 protein increased NFAT-dependent transcriptional activity in the lung, spleen, and liver in NFAT-luc mice. Administration of the NFAT inhibitor A-285222 abolished M1 protein-evoked NFAT activation in the lung, spleen, and liver. M1 protein challenge induced neutrophil recruitment, edema, and CXC chemokine production in the lung, as well as up-regulation of Mac-1 on circulating neutrophils. Inhibition of NFAT activity attenuated M1 protein-induced neutrophil infiltration by 77% and edema formation by 50% in the lung. Moreover, administration of A-285222 reduced M1 protein-evoked pulmonary formation of CXC chemokine >80%. In addition, NFAT inhibition decreased M1 protein-triggered Mac-1 up-regulation on neutrophils. These findings indicate that NFAT signaling controls pulmonary infiltration of neutrophils in response to streptococcal M1 protein via formation of CXC chemokines and neutrophil expression of Mac-1. Thus, the targeting of NFAT activity might be a useful way to ameliorate lung injury in streptococcal infections.
M1血清型的化脓性链球菌可引起中毒性休克综合征（STSS），这与显著的发病率和死亡率相关。本研究的目的是探讨NFAT信号在M1蛋白诱导的肺损伤中的作用。在给予M1蛋白之前，用NFAT抑制剂A - 285222处理NFAT - luc小鼠。在用M1蛋白攻击4小时后，对肺中的中性粒细胞浸润、水肿和CXC趋化因子进行定量。采用流式细胞术测定Mac - 1的表达。用M1蛋白攻击可增加NFAT - luc小鼠肺、脾和肝中NFAT依赖性转录活性。给予NFAT抑制剂A - 285222可消除M1蛋白在肺、脾和肝中引起的NFAT激活。M1蛋白攻击诱导肺中的中性粒细胞募集、水肿和CXC趋化因子产生，以及循环中性粒细胞上Mac - 1的上调。抑制NFAT活性可使M1蛋白诱导的肺中性粒细胞浸润减少77%，水肿形成减少50%。此外，给予A - 285222可使M1蛋白引起的肺CXC趋化因子形成减少>80%。此外，抑制NFAT可降低M1蛋白触发的中性粒细胞上Mac - 1的上调。这些发现表明，NFAT信号通过CXC趋化因子的形成和中性粒细胞Mac - 1的表达来控制对链球菌M1蛋白的肺中性粒细胞浸润。因此，可以通过靶向NFAT活性来改善链球菌感染中的肺损伤。
