Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Julia L.M. Dunn¹  Laurel B. Kartchner¹  Karli Gast²  Marci Sessions¹  Rebecca A. Hunter²  Lance Thurlow¹  Anthony Richardson¹  Mark Schoenfisch²  Bruce A. Cairns¹  Robert Maile¹ 

[1] Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill;Department of Chemistry, The University of North Carolina at Chapel Hill;Department of Surgery, The University of North Carolina at Chapel Hill

关键词: macrophage;    NO;    Pseudomonas aeruginosa;    reactive oxygen and nitrogen species;    TLR;    trauma;   

DOI  :  10.1002/JLB.3AB0616-251RRR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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 hyperresponsiveness in the lung including recruitment of neutrophils with greater ex vivo oxidative activity compared with neutrophils from shaminjured mice. Elevated oxidative function correlated with improved clearance of Pseudomonas aeruginosa, despite down-regulated expression of the bacterial-sensing TLR molecules. Rapamycin administration reversed the burn injury-induced lung innate immune hyperresponsiveness and inhibited enhanced bacterial clearance in burn mice compared with 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 hyperresponsiveness, including neutrophil effector function, allowing normalization of the immune response late after burn injury.

【 授权许可】

CC BY