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.
Humans are constantly exposed to the opportunistic mold and disease caused by this pathogen is often determined by the magnitude of local and systemic immune responses. We have previously shown a protective role for IL-22 after acute exposure. Here, employing IL22R26R reporter mice, we identified iNKT cells, γδ T cells and ILC3 cells as lung cell sources of IL-22 in response to acute exposure. As these cells often utilize common γ-chain cytokines for their development or maintenance, we determined the role of IL-7, IL-21 and IL-15 on lung IL-22 induction and lung clearance. We observed that IL-7, IL-21 and IL-15 were essential, partially required or negatively regulated the production of IL-22, respectively. Deficiency in IL-7 and IL-21, but not IL-15R, resulted in impaired fungal clearance. Surprisingly however, the absence of IL-7, IL-21 or IL-15R signaling had no effect on neutrophil recruitment. The levels of IL-1α, an essential anti- proinflammatory cytokine, were increased in the absence of IL-7 and IL-15R, but decreased in the absence of IL-21. IL-7 was responsible for maintaining lung iNKT cells and γδ T cells whereas IL-21 was responsible for maintaining lung iNKT cells and ILC3s. In contrast, IL-15R deficiency had no effect on the absolute numbers of any IL-22 cell source, rather resulting in enhanced per cell production of IL-22 by iNKT cells and γδ T cells. Collectively, these results provide insight into how the IL-22 response in the lung is shaped after acute exposure.
Individuals that present with difficult-to-control asthma and sensitivity to one or more fungal species are categorized as a subset of severe asthma patients belonging to a group herein referred to as severe asthma with fungal sensitization (SAFS). We have previously reported the identification of numerous cytokines and chemokines that were elevated in human asthmatics that were sensitized to fungi vs. non-fungal sensitized asthmatics. Here, we show that the unique chemokine CX3CL1 (fractalkine) is elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with CX3CL1 in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that the absence of CX3CR1 signaling unexpectedly resulted in a profound impairment in lung function. Histological assessment of lung tissue revealed an unrestricted inflammatory response that was subsequently characterized by enhanced levels of neutrophils, eosinophils and inflammatory monocytes. Neutrophilic inflammation correlated with elevated IL-17A, proinflammatory cytokines (TNF-α, IL-1α IL-1β), neutrophil survival factors (G-CSF) and neutrophil-targeting chemokines (CCL3, CCL4). Eosinophilia correlated with elevated type 2 responses (IL-5, IL-13) whereas inflammatory monocyte levels correlated with elevated type 1 responses (IFN-γ, CXCL9) and survival factors (M-CSF). Despite enhanced inflammatory responses, the immunoregulatory cytokine IL-10 and the natural inhibitor of IL-1 signaling, IL-1RA, were significantly elevated rather than impaired. Regulatory T cell levels were unchanged, as were levels of the anti-inflammatory cytokines IL-35 and IL-38. Taken together, the CX3CL1/CX3CR1 axis preserves lung function during fungal-associated allergic airway inflammation through a non-classical immunoregulatory mechanism.
The authors discovered mislabeled axes in Fig. 6C. Specifically, the y-axis should read "pg/ml (lung digest cells-48 h)" instead of "IL-22 pg/ml (lung digest cells-48 h)." In addition, "IL-1a" and "IL-1b" should be included on the x-axis.
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