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

Abstract

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 sham-injured 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.

Rapamycin for longevity: opinion article

“…A rare side effect of rapamycin is noninfectious interstitial pneumonitis [105]. And by inhibiting neutrophil function, rapamycin may increase the severity of bacterial infections [106]. These side effects require rapamycin’s discontinuation.…”

Burn Injury Induces Proinflammatory Plasma Extracellular Vesicles That Associate with Length of Hospital Stay in Women: CRP and SAA1 as Potential Prognostic Indicators

“…Compared to sham, burn EVs robustly induced secretion of IL-6 (35-fold, *** p < 0.001, Figure 2 A), MCP-1 (6-fold, ** p < 0.01, Figure 2 B), IL-12p70 (400-fold, * p < 0.05, Figure 2 C) and IFNγ (7-fold, * p < 0.05, Figure 2 D). These cytokines are also found to be increased peripherally early (~1–3 days) after burn injury in human burn patients and mouse models [ 4 , 5 , 7 , 8 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

Kakonein restores diabetes‐induced endothelial junction dysfunction via promoting autophagy‐mediated NLRP3 inflammasome degradation

“…In addition, the autophagy inhibitor 3‐methyladenine significantly increased the expression of NLRP3, thereby confirming our hypothesis (Figure ). Although rapamycin could significantly increase the level of autophagy in cells, its adverse effects are often reported, such as stomatitis and myositis 37 ; non‐infectious interstitial pneumonitis and increasing the severity of bacterial infections 38 ; anaemia and leukopenia 39 . On the contrary, kakonein has been used in the clinical adjuvant treatment of cardiovascular‐related diseases in China 40 .…”