PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils.
PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils.
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蛋白酪氨酸磷酸酶1B（PTP1B）抑制剂可预防急性肺损伤，并调节中性粒细胞中的CXC趋化因子受体4（CXCR4）信号通路。
DOI：
10.1172/jci.insight.158199
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发表时间：
2022-07-22
期刊：
影响因子：
8
通讯作者：
Tonks, Nicholas K.
中科院分区：
文献类型：
--
作者：
Song, Dongyan;Adrover, Jose M.;Felice, Christy;Christensen, Lisa N.;He, Xue-Yan;Merrill, Joseph R.;Wilkinson, John E.;Janowitz, Tobias;Lyons, Scott K.;Egeblad, Mikala;Tonks, Nicholas K.
急性肺损伤（ALI）可引发急性呼吸窘迫综合征（ARDS），这是一种致命病症，治疗手段有限，目前也是全球范围内由新冠病毒感染导致死亡的常见原因。输血相关性急性肺损伤（TRALI）继发的ARDS已在临床前通过向脂多糖（LPS）致敏的小鼠注射抗MHC-I抗体得以模拟。在该模型中，我们证实蛋白酪氨酸磷酸酶1B（PTP1B）抑制剂可预防肺损伤并提高生存率。PTP1B是一种调节对体内平衡和炎症至关重要的信号通路的蛋白酪氨酸磷酸酶。使用PTP1B抑制剂进行治疗可减弱驱动ALI的异常中性粒细胞功能，这与髓过氧化物酶的释放减少、中性粒细胞胞外诱捕网（NET）形成受抑制以及中性粒细胞迁移受抑制相关。从机制上讲，通过趋化因子受体CXCR4的信号传导减少，尤其是对PI3Kγ/AKT/mTOR激活的影响，对这些效应至关重要，这将PTP1B抑制与促进中性粒细胞呈现衰老表型联系起来。鉴于中性粒细胞的失调激活与脓毒症有关并会造成附带的组织损伤，我们证明PTP1B抑制剂在LPS诱导的脓毒症模型中提高了生存率并改善了肺损伤，在盲肠结扎穿孔诱导（CLP诱导）的脓毒症模型中也提高了生存率。我们的数据凸显了抑制PTP1B对于预防多种病因导致的ALI和ARDS的潜力。
Acute lung injury (ALI) can cause acute respiratory distress syndrome (ARDS), a lethal condition with limited treatment options and currently a common global cause of death due to COVID-19. ARDS secondary to transfusion-related ALI (TRALI) has been recapitulated preclinically by anti–MHC-I antibody administration to LPS-primed mice. In this model, we demonstrate that inhibitors of PTP1B, a protein tyrosine phosphatase that regulates signaling pathways of fundamental importance to homeostasis and inflammation, prevented lung injury and increased survival. Treatment with PTP1B inhibitors attenuated the aberrant neutrophil function that drives ALI and was associated with release of myeloperoxidase, suppression of neutrophil extracellular trap (NET) formation, and inhibition of neutrophil migration. Mechanistically, reduced signaling through the CXCR4 chemokine receptor, particularly to the activation of PI3Kγ/AKT/mTOR, was essential for these effects, linking PTP1B inhibition to promoting an aged-neutrophil phenotype. Considering that dysregulated activation of neutrophils has been implicated in sepsis and causes collateral tissue damage, we demonstrate that PTP1B inhibitors improved survival and ameliorated lung injury in an LPS-induced sepsis model and improved survival in the cecal ligation and puncture–induced (CLP-induced) sepsis model. Our data highlight the potential for PTP1B inhibition to prevent ALI and ARDS from multiple etiologies.
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