IL-33 signaling regulates innate IL-17A and IL-22 production via suppression of PGE2 during lung fungal infection

• Published in: The Journal of immunology (1950) Vol. 199; no. 6; pp. 2140 - 2148
• Main Authors: Garth, Jaleesa M., Reeder, Kristen M., Godwin, Matthew S., Mackel, Joseph J., Dunaway, Chad W., Blackburn, Jonathan P., Steele, Chad
• Format: Journal Article
• Language: English
• Published: 07.08.2017
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1602186

Members of the IL-1 family play protective and regulatory roles in immune defense against the opportunistic mold Aspergillus fumigatus . Here, we investigated the IL-1 family member IL-33 in lung defense against A. fumigatus . IL-33 was detected in the naïve 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 fungal-exposed Il1rl1 −/− mice. Subsequently, IL-33 administration to normal mice attenuated fungal-induced IL-17A and IL-22, but not IL-1α, IL-1β and IL-6 production. IL-33 mediated regulation of IL-17A and IL-22 did not involve the modulation of IL-23 but rather prostaglandin E2 (PGE2); PGE2 was significantly increased in fungal-exposed Il1rl1 −/− mice and normal mice produced less PGE2 after fungal exposure when administered IL-33, suggesting that IL-33 mediated regulation of IL-17A and IL-22 occurred at the level of PGE2. This was confirmed by in vivo cyclooxygenase 2 (COX-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 PGE2 receptor agonist increased, whereas a PGE2 synthase inhibitor decreased, the levels of IL-17A and IL-22, but not IL-1α, IL-1β and IL-6. This study establishes novel mechanisms of induction of innate IL-17A/IL-22 production via PGE2 and regulation of the PGE2-IL-17A-IL-22 axis via IL-33 signaling during lung fungal exposure.