Dectin-1-dependent interleukin-22 contributes to early innate lung defense against Aspergillus fumigatus.
We have previously reported that mice deficient in the beta-glucan receptor Dectin-1 displayed increased susceptibility to Aspergillus fumigatus lung infection in the presence of lower interleukin 23 (IL-23) and IL-17A production in the lungs and have reported a role for IL-17A in lung defense. As IL-23 is also thought to control the production of IL-22, we examined the role of Dectin-1 in IL-22 production, as well as the role of IL-22 in innate host defense against A. fumigatus. Here, we show that Dectin-1-deficient mice demonstrated significantly reduced levels of IL-22 in the lungs early after A. fumigatus challenge. Culturing cells from enzymatic lung digests ex vivo further demonstrated Dectin-1-dependent IL-22 production. IL-22 production was additionally found to be independent of IL-1β, IL-6, or IL-18 but required IL-23. The addition of recombinant IL-23 augmented IL-22 production in wild-type (WT) lung cells and rescued IL-22 production by lung cells from Dectin-1-deficient mice. In vivo neutralization of IL-22 in the lungs of WT mice resulted in impaired A. fumigatus lung clearance. Moreover, mice deficient in IL-22 also demonstrated a higher lung fungal burden after A. fumigatus challenge in the presence of impaired IL-1α, tumor necrosis factor alpha (TNF-α), CCL3/MIP-1α, and CCL4/MIP-1β production and lower neutrophil recruitment, yet intact IL-17A production. We further show that lung lavage fluid collected from both A. fumigatus-challenged Dectin-1-deficient and IL-22-deficient mice had compromised anti-fungal activity against A. fumigatus in vitro. Although lipocalin 2 production was observed to be Dectin-1 and IL-22 dependent, lipocalin 2-deficient mice did not demonstrate impaired A. fumigatus clearance. Moreover, lung S100a8, S100a9, and Reg3g mRNA expression was not lower in either Dectin-1-deficient or IL-22-deficient mice. Collectively, our results indicate that early innate lung defense against A. fumigatus is mediated by Dectin-1-dependent IL-22 production.
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Melissa A
MA
Gessner
Jessica L
JL
Werner
Lauren M
LM
Lilly
Michael P
MP
Nelson
Allison E
AE
Metz
Chad W
CW
Dunaway
Yvonne R
YR
Chan
Wenjun
W
Ouyang
Gordon D
GD
Brown
Casey T
CT
Weaver
Chad
C
Steele
D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D007378:Interleukins / Q000276:immunology*; D037181:Lectins, C-Type / Q000172:deficiency / Q000378:metabolism*; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D055732:Pulmonary Aspergillosis / Q000276:immunology*; D000097043:Interleukin-22; D000099181:Dectin-1
D007378:Interleukins; D037181:Lectins, C-Type; D000097043:Interleukin-22; D000099181:Dectin-1