Article Text


Novel mechanisms driving airway inflammation in asthma
S35 Rapamycin inhibits IL-33-induced, nuocyte-driven airway inflammation
  1. A S Mirchandani,
  2. R J Salmond,
  3. C J Bain,
  4. F Y Liew
  1. University of Glasgow, Glasgow, UK


Introduction IL-33 is an innate cytokine that promotes Th2 responses in both the innate and the adaptive immune systems, with an established role in allergic airway inflammation.1 The signalling pathway of IL-33/ ST2 is incompletely understood and the cells driving IL-33-mediated inflammation have remained elusive. Nuocytes, also known as natural helper cells, are a novel subpopulation of lineage negative innate cells that respond to IL-33 and IL-2.2 Rapamycin is a macrolide antibiotic that allosterically blocks mTOR, a serine-threonine kinase involved in numerous cellular signalling pathways.

Aim To determine the role of mTOR in IL-33-induced airway inflammation and the effect of rapamycin on IL-33-induced nuocytes in the lung.

Method BALB/c mice were treated with 1 μg of IL-33 intranasally for 5 consecutive days in the presence or absence of rapamycin. Bronchoalveolar lavage (BAL) for cellular and cytokine analysis was performed. Fluorescence-activated cell sorting (FACS) of lung digests were analysed for intracellular IL-5 and cell surface markers.

Results IL-33 induced profound airway cellular infiltration noted in the BAL that was significantly inhibited by rapamycin. Cytokine levels from BAL fluid were also significantly reduced in mice treated with IL-33+ rapamycin. FACS analysis of lung digests demonstrated that IL-33 induced the expansion of lineage negative cells, in keeping with a population of nuocytes, which were the main source of IL-5 in the lung. Furthermore, this population of cells was suppressed by rapamycin.

Discussion Intranasal IL-33 drives mTOR-dependant airway inflammation. Nuocytes are the main source of IL-5 in IL-33-driven airway inflammation. Rapamycin inhibits the production of IL-5 and IL-13 in vivo as well as the expansion of nuocytes in the lung.

Abstract S35 Figure 1

BALB/c mice were treated intranasally with 1 μg IL-33 in the presence or absence of 1 mg/kg rapamycin for 5 consecutive days. The mice were sacrificed on day 6 and BAL total cell counts were performed. ***=p<0.001.

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