IL-33 induces innate lymphoid cell-mediated airway inflammation by activating mammalian target of rapamycin.
BACKGROUND
The IL-1 family cytokine IL-33 is involved in the induction of airway inflammation in allergic patients and after viral infection. Several cell types, including CD4(+) T(H)2 cells and the recently described type 2 innate lymphoid cells (ILCs), are targets for IL-33, yet the mechanisms by which this cytokine modulates their activation are not clear.


OBJECTIVE
Our goal was to investigate a role for mammalian target of rapamycin (mTOR) signaling in the activation of T(H)2 and ILC responses and the induction of airway inflammation by IL-33.


METHODS
We biochemically determined the effect of IL-33 on mTOR activation in T(H)2 cells and ILCs and examined the effect of this signaling pathway in vivo using a murine model of IL-33-induced lung inflammation.


RESULTS
We found that IL-33 induces mTOR activation through p110δ phosphoinositide 3-kinase and that blockade of the mTOR pathway inhibited IL-33-induced IL-5 and IL-13 production by T(H)2 cells and ILCs. Furthermore, use of a ribosomal protein S6 kinase 1 inhibitor implicated a role for ribosomal protein S6 kinase 1 in IL-33-induced mTOR-dependent cytokine production. Intranasal administration of IL-33 to wild-type mice induced airway inflammation, whereas adoptive transfer of wild-type ILCs to IL-33 receptor-deficient (St2(-/-)) mice recapitulated this response. Importantly, coadministration of the mTOR inhibitor rapamycin reduced IL-33-dependent ILC, macrophage, and eosinophil accumulation; cytokine secretion; and mucus deposition in the airways.


CONCLUSIONS
These data reveal a hitherto unrecognized role of mTOR signaling in IL-33-driven, ILC-dependent inflammation in vivo and suggest that manipulation of this pathway might represent a target for therapeutic intervention for airway inflammation.
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom.
Robert J
RJ
Salmond
Ananda S
AS
Mirchandani
Anne-Gaelle
AG
Besnard
Calum C
CC
Bain
Neil C
NC
Thomson
Foo Y
FY
Liew
D000818:Animals; D002478:Cells, Cultured; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13 / Q000378:metabolism; D000067596:Interleukin-33; D015848:Interleukin-5 / Q000378:metabolism; D007378:Interleukins / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D018123:Receptors, Interleukin / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation
C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D018123:Receptors, Interleukin; C546843:mTOR protein, mouse; D058543:Class Ia Phosphatidylinositol 3-Kinase; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases