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The role of mTOR activation in steroid-resistant asthma: insights from particulate matter-induced mouse model and
Heung-Woo Park1,2, Suh-Young Lee1, Hyun Seung Lee3
1Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Abstract:
Particulate matter (PM) exposure has been proposed as one of the causes of steroid resistance. However, studies investigating this using patient samples or animals are still lacking. Therefore, in this study, we aimed to investigate the changes in cytokines and mTOR (mammalian target of rapamycin) activation in patients with steroid resistant asthma and the role of mTOR in a mouse model of steroid resistant asthma induced by PM. In mouse experiment, on administering PM10 and allergen (Dp) through the intranasal route for 3 weeks, airway hyperresponsiveness (AHR), eosinophils, and airway inflammation were increased. However, administering rapamycin (mTOR inhibitor) together with PM and Dp led to significant decrease in all of the abovementioned features; additionally, the population of IL-13 + or IL-17 + cells in CD62lowCD44high subset of CD4 + T cells, which serves as an effector/memory cell marker, showed a significant decrease when compared to the group that received PM and Dp. When Dp was administered once after a rest period, the mice exposed to PM and Dp exhibited resurgence in asthma features and elevated effector/memory IL-13 + or IL-17 + cell populations. Rapamycin administration inhibited this effect. In human PBMC, in the steroid Non-Responder (NR) group, cytokines with p-mTOR double-positive population of effector/memory CD4 T cells (CCR7-CD45RA-CD4 + in CD62-CD27-CD45RO+) was significantly higher than that of the Normal or steroid Responder (R) groups. These data demonstrates that rapamycin can inhibit asthmatic features in mouse model of PM induced steroid-resistant asthma. And we suggest that rapamycin could act on effector/memory CD4 + T cells through in vitro and patient sample experiments.
Insights
Particulate matter exposure worsens steroid-resistant asthma by activating mTOR. Rapamycin, an mTOR inhibitor, reduced asthma symptoms in mice and may target effector/memory T cells in patients.
Area of Science:
- Immunology
- Respiratory Medicine
- Pharmacology
Background:
- Steroid resistance is a challenge in asthma management.
- Particulate matter (PM) exposure is a potential trigger for steroid resistance.
- Limited studies exist on PM's role and therapeutic targets in steroid-resistant asthma.
Purpose of the Study:
- Investigate cytokine changes and mTOR activation in steroid-resistant asthma patients.
- Elucidate the role of mTOR in a PM-induced mouse model of steroid-resistant asthma.
- Assess rapamycin's therapeutic potential in this model.
Main Methods:
- Induced steroid-resistant asthma in mice using PM10 and allergen (Dp) intranasally.
- Administered rapamycin (mTOR inhibitor) to assess its effects on asthma features.
- Analyzed airway hyperresponsiveness, inflammation, eosinophils, and specific T cell populations (IL-13+, IL-17+ in CD4+ effector/memory cells).
- Examined peripheral blood mononuclear cells (PBMCs) from human asthma patients (responders vs. non-responders).
Main Results:
- PM exposure increased airway hyperresponsiveness, eosinophils, and inflammation in mice.
- Rapamycin treatment significantly reduced these asthma features.
- Rapamycin decreased IL-13+/IL-17+ CD4+ effector/memory T cells.
- PM-exposed mice showed asthma feature resurgence after a rest period, which rapamycin inhibited.
- Steroid-non-responder patients had higher p-mTOR positive effector/memory CD4+ T cells compared to controls.
Conclusions:
- Rapamycin effectively inhibits asthmatic features in a PM-induced mouse model of steroid-resistant asthma.
- mTOR activation in effector/memory CD4+ T cells is implicated in steroid-resistant asthma.
- Rapamycin shows therapeutic promise for steroid-resistant asthma, potentially by modulating these T cells.
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