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

Abstract

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-1␤, 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-1␣, tumor necrosis factor alpha (TNF-␣), CCL3/MIP-1␣, and CCL4/MIP-1␤ 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.

Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis

“…32 In this regard, IL-22 was recently found to be produced in response to A. fumigatus by a dectin-1-dependent mechanism. 33 In combination with IL-17A, IL-22 has been found to be crucially involved in the control of Candida growth in the gastrointestinal tract in conditions of Th1 and Th17 deficiency. 23 Moreover, vaginal epithelial cells also produced S100A8 and S100A9 following interaction with Candida, 34 suggesting the possible involvement of IL-22 in vaginal candidiasis.…”

Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease

“…This was consistent with the report that C. albicans could also exacerbate DSSinduced colitis [163] and that an indigenous Candida population could drive disease. Similarly, lung responses generated via the β-glucan receptor dectin-1 are required for lung defense during acute, invasive A. fumigatus infection through IL-22 production [164]. Unexpectedly, lung responses generated via dectin-1, in an allergic mouse model of chronic lung exposure to live A. fumigatus conidia, lead to the induction of multiple proallergic (Muc5ac, Clca3, CCL17, CCL22, and IL-33) and proinflammatory (IL-1β and CXCL1) mediators that compromised lung function [165].…”

Characterization of IL-22 and antimicrobial peptide production in mice protected against pulmonary Cryptococcus neoformans infection

“…Secretion of lipocalin-2 involves signalling via Toll-like receptor 4 (TLR4) and subsequent NF-kB binding to consensus sequences upstream of the lipocalin-2 promoter (Flo et al, 2004;Li & Chan, 2011), and its production is regulated via IL-1b, IL-17A and other cytokines (Chan et al, 2009;Kolls et al, 2008;Li & Chan, 2011). Although lipocalin-2 is increased in the lungs of mice during infection with Aspergillus fumigatus, lipocalin-2-deficient mice do not demonstrate impaired fungal clearance (Gessner et al, 2012), and lipocalin-2 does not bind to fungal siderophores (Flo et al, 2004). Thus, lipocalin-2 may only serve as a biomarker for inflammatory immune responses against fungi and may not have any direct fungicidal effects, although its role against C. neoformans remains to be determined.…”

“…Mice immunized with H99c are completely protected against a subsequent pulmonary challenge with an otherwise lethal WT C. neoformans strain (Wormley et al, 2007;Wozniak et al, 2009). IL-17A and IL-22 function cooperatively to induce the production of antimicrobial peptides and acute phase proteins such as b-defensins, S100A8, S100A9 and lipocalin-2 in bronchial epithelial cells (Aujla et al, 2008;Gessner et al, 2012;Kolls et al, 2008;Liang et al, 2006;Wolk et al, 2011). Studies have shown the importance of IL-17A and IL-22 clinically to mediate clearance in patients with chronic mucocutaneous candidiasis (Eyerich et al, 2008) and experimentally to protect mice against disseminated candidiasis (Huang et al, 2004), pulmonary aspergillosis (Gessner et al, 2012) and pulmonary Klebsiella pneumoniae infection (Aujla et al, 2008).…”

“…IL-17A and IL-22 function cooperatively to induce the production of antimicrobial peptides and acute phase proteins such as b-defensins, S100A8, S100A9 and lipocalin-2 in bronchial epithelial cells (Aujla et al, 2008;Gessner et al, 2012;Kolls et al, 2008;Liang et al, 2006;Wolk et al, 2011). Studies have shown the importance of IL-17A and IL-22 clinically to mediate clearance in patients with chronic mucocutaneous candidiasis (Eyerich et al, 2008) and experimentally to protect mice against disseminated candidiasis (Huang et al, 2004), pulmonary aspergillosis (Gessner et al, 2012) and pulmonary Klebsiella pneumoniae infection (Aujla et al, 2008). S100A8 and S100A9, which can collectively form a heterodimer called calprotectin (Lagasse & Clerc, 1988;Odink et al, 1987;Zwadlo et al, 1988), are involved in neutrophil recruitment and are known to be produced by epithelial cells following induction by IL-22 (Aujla et al, 2008;Kolls et al, 2008;Liang et al, 2006).…”