Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury.
Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury.
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DOI：
10.1002/jlb.3ab0616-251rrr
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发表时间：
2018-05
影响因子：
5.5
通讯作者：
Maile R
中科院分区：
文献类型：
--
作者：
Dunn JLM;Kartchner LB;Gast K;Sessions M;Hunter RA;Thurlow L;Richardson A;Schoenfisch M;Cairns BA;Maile R
Bacterial pneumonia is a leading cause of death late after burn injury due to the severe immune dysfunction that follows this traumatic injury. The Mechanistic/Mammalian Target of Rapamycin (mTOR) pathway drives many effector functions of innate immune cells required for bacterial clearance. Studies have demonstrated alterations in multiple cellular processes in patients and animal models following burn injury in which mTOR is a central component. Goals of this study were to 1) investigate the importance of mTOR signaling in antimicrobial activity by neutrophils and 2) therapeutically target mTOR to promote normalization of the immune response. We utilized a murine model of 20% total body surface area burn and the mTOR-specific inhibitor rapamycin. Burn injury led to innate immune hyper-responsiveness in the lung including recruitment of neutrophils with greater ex vivo oxidative activity compared to neutrophils from sham injured mice. Elevated oxidative function correlated with improved clearance of Pseudomonas aeruginosa, despite downregulated expression of the bacterial-sensing Toll-Like Receptor (TLR) molecules. Rapamycin administration reversed the burn injury-induced lung innate immune hyper-responsiveness and inhibited enhanced bacterial clearance in burn mice compared to untreated burn mice, resulting in significantly higher mortality. Neutrophil ex vivo oxidative burst was decreased by rapamycin treatment. These data indicate that 1) neutrophil function within the lung is more important than recruitment for bacterial clearance following burn injury and 2) mTOR inhibition significantly impacts innate immune hyper-responsiveness, including neutrophil effector function, allowing normalization of the immune response late after burn injury.
