IL-33 signaling regulates innate IL-17A and IL-22 production via suppression of prostaglandin E2 during lung fungal infection

Academic Article

Abstract

  • Members of the IL-1 family play protective and regulatory roles in immune defense against the opportunistic mold Aspergillus fumigatus. In this study, we investigated the IL-1 family member IL-33 in lung defense against A. fumigatus. IL-33 was detected in the naive lung, which further increased after exposure to A. fumigatus in a dectin-1-independent manner. Mice deficient in the receptor for IL-33 (Il1rl1 ) unexpectedly demonstrated enhanced lung clearance of A. fumigatus. IL-33 functioned as a negative regulator of multiple inflammatory cytokines, as IL-1α, IL-1β, IL-6, IL-17A, and IL-22 were significantly elevated in fungalexposed Il1rl1 mice. Subsequently, IL-33 administration to normal mice attenuated fungal-induced IL-17A and IL-22, but not IL-1α, IL-1β, or IL-6, production. IL-33-mediated regulation of IL-17A and IL-22 did not involve the modulation of IL-23 but rather PGE ; PGE was significantly increased in fungal-exposed Il1rl1 mice, and normal mice produced less PGE after fungal exposure when administered IL-33, suggesting that IL-33-mediated regulation of IL-17A and IL-22 occurred at the level of PGE . This was confirmed by in vivo cyclooxygenase 2 inhibition, which attenuated fungal-induced IL-17A and IL-22, as well as IL-1α, IL-1β, and IL-6, production in Il1rl1 mice, resulting in impaired fungal clearance. We also show that a PGE receptor agonist increased, whereas a PGE synthase inhibitor decreased, the levels of IL-17A and IL-22 but not IL-1α, IL-1β, or IL-6. This study establishes novel mechanisms of innate IL-17A/IL-22 production via PGE and regulation of the PGE /IL-17A/IL-22 axis via IL-33 signaling during lung fungal exposure. -/- -/- -/- -/- 2 2 2 2 2 2 2 2
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    Digital Object Identifier (doi)

    Author List

  • Garth JM; Reeder KM; Godwin MS; Mackel JJ; Dunaway CW; Blackburn JP; Steele C
  • Start Page

  • 2140
  • End Page

  • 2148
  • Volume

  • 199
  • Issue

  • 6