Dectin-1-Dependent Interleukin-22 Contributes to Early Innate Lung Defense against Aspergillus fumigatus

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Infection and immunity (Impact Factor: 3.73). 01/2012; 80(1):410-7. DOI: 10.1128/IAI.05939-11
Source: PubMed


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.

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Available from: Michael Nelson, Jan 12, 2015
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    • "Genomic DNA was extracted from 50–100 mg freeze dried, homogenized whole lung tissue using a previously described DNA extraction buffer for Aspergillus nucleic acids with subsequent phenol/chloroform extraction. A total of 500 ng genomic DNA was used for quantitative PCR to determine the fungal DNA content [56], [57]. A qPCR fungal burden assay was performed to determine the amount of fungal 18S rDNA in lung extracts with 18S rDNA primer and probe sets with a modified probe quencher (5′-/56-FAM/AGC CAG CGG/ZEN/CCC GCA AAT G/3IABkFQ/-3′) [56], [58]. "
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    ABSTRACT: The ubiquitous fungal pathogen Aspergillus fumigatus is a mediator of allergic sensitization and invasive disease in susceptible individuals. The significant genetic and phenotypic variability between and among clinical and environmental isolates are important considerations in host-pathogen studies of A. fumigatus-mediated disease. We observed decreased radial growth, rate of germination, and ability to establish colony growth in a single environmental isolate of A. fumigatus, Af5517, when compared to other clinical and environmental isolates. Af5517 also exhibited increased hyphal diameter and cell wall β-glucan and chitin content, with chitin most significantly increased. Morbidity, mortality, lung fungal burden, and tissue pathology were decreased in neutropenic Af5517-infected mice when compared to the clinical isolate Af293. Our results support previous findings that suggest a correlation between in vitro growth rates and in vivo virulence, and we propose that changes in cell wall composition may contribute to this phenotype.
    PLoS ONE 06/2014; 9(6):e100430. DOI:10.1371/journal.pone.0100430 · 3.23 Impact Factor
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    • "Mouse-based studies have revealed that Th17 cells co-express IL-22, which plays an important role in antimicrobial responses and autoimmune diseases [21]. Similarly, in humans, IL-22 was demonstrated to be up-regulated during defense responses against fungal infections [22]. "
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    ABSTRACT: In recent years, the fungal infectious disease zygomycosis has increased in incidence worldwide, especially among the immunodeficient population. Despite the rates of zygomycosis-related death and deformation being very high, the mechanism(s) by which the fungal pathogens cause these severe manifestations remain unknown. Using the associated Rhizomucor variabilis species, which can selectively induce cutaneous zygomycosis in otherwise healthy individuals, we investigated the host mechanisms of infection-related responses, including cytokine and chemokine expression as well as contributions of particular T cell subsets. siRNA specifically targeting IL-22,IL-17 and IFN-γ were used to down-regulate expression of those molecules. In mouse models of infection, IL-22 was implicated in development of Rhizomucor spp.-induced skin lesions. In cultured human peripheral blood monocytes, R. pusilluscan, which is often found in immunodeficient patients, induced the production of IL-22, while R. variabilis did not. Moreover, Rhizomucor spp.-induced secretion of Il-22 from CCR6(+)CCR4(+)CCR10(+) cells was down-regulated by knockdown of IL-22 related signaling receptors, RORC and ARH. Our data strongly suggest that avoidance of IL-22 may be one mechanism by which mucor species produce morbidity and mortality in infected individuals.
    PLoS ONE 06/2013; 8(6):e65065. DOI:10.1371/journal.pone.0065065 · 3.23 Impact Factor
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    • "Based on the observation that levels of IL-22 and IL-22 receptor were elevated in AVMC, we examined the efficacy of IL-22 in the AVMC mouse model, with the use of anti-IL-22 antibody (Anti-IL-22Ab) [20,25]. Functional studies in human or murine model systems have indicated that IL-22 could be either pathologic or protective, depending on the context in which it was expressed [17,18,22,26,27]. Our results proved that neutralization of IL-22 exacerbated the severity of AVMC, which was verified by the lower survive rate, higher values of HW/BW and pathological scores of heart sections. "
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    ABSTRACT: Background Recently, a new subset of T helper (Th) cell that predominantly secret cytokine interleukin-22 (IL-22) is identified, termed Th22 cells. The Th22 subset has been demonstrated to be involved in immunity and tissue inflammation. However, the existence of Th22 cells and role of IL-22 in acute viral myocarditis (AVMC) remain unknown. Methods BALB/c mice were intraperitoneally (i.p) infected with CVB3 for establishing AVMC models. Control mice were treated with phosphate-buffered saline (PBS) i.p. On day 14 post injection, frequencies of splenic Th22 cells were determined, productions of IL-22 and expressions of IL-22R (IL-22 receptor) were measured. To further investigate the effects of IL-22, AVMC mice treated with Anti-IL-22 neutralizing antibody were explored. The severity of AVMC were monitored; the frequencies of Th22 cells, the expressions of IL-22 and IL-22R were investigated; in addition to IFN-γ, inflammatory cytokines IL-17, TNF-α, IL-6 as well as IL-1β, were evaluated. Cardiac viral replication were detected. Results Compared with control group, significant elevations of circulating Th22 cells and IL-22, cardiac protein and mRNA of IL-22, and IL-22R1 were demonstrated in AVMC group. Treatment of AVMC mice with Anti-IL-22 Ab exacerbated the severity of viral myocarditis, verified by lower survival rate, higher HW/BW ratios and cardiac pathological scores. Anti-IL-22 Ab decreased the frequencies of Th22 cells and the levels of IL-22, and increased the expressions of cardiac IL-22R1. Up-regulations of IL-17, IL-6 and TNF-α, down-regulations of IFN-γ proteins and gene expressions in the plasma and myocardium, were observed in Anti-IL-22 Ab group. Furthermore, neutralization of IL-22 significantly promoted cardiac viral replication. Conclusions Our data indicate that the increased frequencies of IL-22-producing Th22 cells may play an important role in the pathogenesis of CVB3-induced mice AVMC, IL-22 may act as an myocardium-protective cytokine via the IL-22–IL-22R pathway, and suggest that targeting the Th22 cell and IL-22–IL-22R pathway could provide new therapeutic modalities for the treatment of CVB3-induced AVMC.
    Virology Journal 10/2012; 9(1):232. DOI:10.1186/1743-422X-9-232 · 2.18 Impact Factor
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