Paradoxical Effects of Rapamycin on Experimental House Dust Mite-Induced Asthma

Abstract

The mammalian target of rapamycin (mTOR) modulates immune responses and cellular proliferation. The objective of this study was to assess whether inhibition of mTOR with rapamycin modifies disease severity in two experimental murine models of house dust mite (HDM)-induced asthma. In an induction model, rapamycin was administered to BALB/c mice coincident with nasal HDM challenges for 3 weeks. In a treatment model, nasal HDM challenges were performed for 6 weeks and rapamycin treatment was administered during weeks 4 through 6. In the induction model, rapamycin significantly attenuated airway inflammation, airway hyperreactivity (AHR) and goblet cell hyperplasia. In contrast, treatment of established HDM-induced asthma with rapamycin exacerbated AHR and airway inflammation, whereas goblet cell hyperplasia was not modified. Phosphorylation of the S6 ribosomal protein, which is downstream of mTORC1, was increased after 3 weeks, but not 6 weeks of HDM-challenge. Rapamycin reduced S6 phosphorylation in HDM-challenged mice in both the induction and treatment models. Thus, the paradoxical effects of rapamycin on asthma severity paralleled the activation of mTOR signaling. Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin. We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma. Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma.

Commentary: IL-4 and IL-13 receptors and signaling

“…(182) repeated early studies by Fredricksson et al . (183) comparing the effects of rapamycin treatment during the induction phase of allergic lung inflammation versus established disease. Mushaben and colleagues described the importance of mTORC1-mediated signaling in promoting the early phases of allergic disease using the house dust mite (HDM)-induced allergic inflammation model in mice.…”

“…There was no effect on AHR in the most recent study (182). In fact, AHR and airway inflammation became worse when rapamycin was given to animals with established allergic lung inflammation (183). Uncovering more details of the precise molecular underpinnings of mTORC1 or mTORC2 regulation to subvert pathogenic IL-4 signaling in allergic inflammation will aid in more effective manipulation of these pathways for therapeutic benefit.…”

Proteomics profiling reveals inflammatory biomarkers of antidepressant treatment response: Findings from the CO-MED trial

“…A putative biological mechanism underlying the association between increased Eotaxin-1 and remission is that it may reflect increased levels of mammalian targets of rapamycin (mTOR) protein. Inhibition of mTOR has been shown to reduce levels of Eotaxin-1 in animal models (Fredriksson et al, 2012; Mushaben et al, 2011). Additionally, rapid activation of the mTOR signaling pathway is reportedly related to synaptogenesis and the rapid-antidepressant effects of ketamine (Li et al, 2010).…”

The Very Low Density Lipoprotein Receptor Attenuates House Dust Mite–Induced Airway Inflammation by Suppressing Dendritic Cell–Mediated Adaptive Immune Responses

“…Quantitative real time-polymerase chain reaction (qRT-PCR) was performed as previously described (21). Lungs were minced into 1 mm pieces and stored in RNAlater (Ambion, Austin, TX) at −80°C prior to isolation of total RNA using a lipid tissue kit (Qiagen Inc, Valencia, CA).…”

“…Single cell suspensions of mediastinal lymph nodes (MLN) from HDM-challenged mice were prepared by passing disrupted lymph nodes through a 100 μm strainer, as previously described (21). Following lysis of red blood cells using ACK buffer, MLN cells were suspended in RPMI 1640 medium containing 10% fetal calf serum, penicillin (50 units/ml), streptomycin (50 μg/ml), and L-glutamine (2 mM) and 4 × 10 6 cells per well were cultured in 96-well plates with “U”-shaped bottoms.…”