The IL‐36 receptor pathway regulates Aspergillus fumigatus‐induced Th1 and Th17 responses

Abstract

IL-1 drives Th responses, particularly Th17, in host defense. Sharing the same coreceptor, the IL-1 family member IL-36 exhibits properties similar to those of IL-1. In the present study, we investigated the role of IL-36 in Aspergillus fumigatus-induced human Th responses. We observed that different morphological forms of A. fumigatus variably increase steady-state mRNA of IL-36 subfamily members. IL-36α is not significantly induced by any morphological form of Aspergillus. Most strikingly, IL-36γ is significantly induced by live A. fumigatus conidia and heat-killed hyphae, whereas IL-36Ra (IL-36 receptor antagonist) is significantly induced by heat-killed conidia, hyphae, and live conidia. We also observed that IL-36γ expression is dependent on the dectin-1/Syk and TLR4 signaling pathway. In contrast, TLR2 and CR3 inhibit IL-36γ expression. IntroductionThe IL-1 family (IL-1F) consists of 11 members [1]. The in silico discovery of IL-1 family members IL-1F5, IL-1F6, IL-1F8, and IL-1F9 have recently been renamed IL-36 receptor antagonist (IL-36Ra), IL-36α, IL-36β, and IL-36γ, respectively. Presently, there is a paucity of data on the biological properties and functional roles of the IL-36 subfamily in health and disease. The clasCorrespondence: Dr. Frank L. van de Veerdonk e-mail: f.veerdonk@aig.umcn.nl sic IL-1 family members IL-1α and IL-1β as well as IL-18 and IL-33 polarize Th responses [1]. However, little is known about the role of the IL-36 subfamily (IL-36α, IL-36β, and IL-36γ) and the IL-36Ra in antimicrobial host defense. Each member of the IL-36 subfamily binds to IL-1Rrp2 (now renamed IL-36 receptor, IL-36R) and recruits the co-receptor for signal transduction, IL-1RAcP [2,3]. The IL-36R is expressed on dendritic cells (DCs) [4,5] and T cells [5]. Stimulation of T cells by IL-36R ligands results in the induction of , and DCs primed with IL-36 ligands are inducers of Th1 cells. Although the synthetic TLR3 ligand polyI:C induces IL-36γ secretion [6], nothing is known about the innate pattern recognition pathways that induce IL-36R ligands in the antimicrobial host defense.www.eji-journal.eu Eur. J. Immunol. 2013. 43: 416-426 Immunity to infection 417The opportunistic fungus Aspergillus fumigatus is ubiquitous; Aspergillus spores are inhaled daily by humans. Inhaled Aspergillus spores (conidia) are efficiently cleared in healthy individuals [7]. However, in immunocompromised persons, or in patients with preexisting lung injury, Aspergillus conidia germinate resulting in invasive infections associated with high mortality [8]. Th responses are important in the host defense against invasive aspergillosis [9], and the major known cytokine pathways that are involved in the induction of Th1 and Th17 responses are IL-12/IL-18 and IL-1/IL-23, respectively [9,10]. Next to the induction of the specific Th-axis, there is also interplay between these cytokine pathways. IFN-γ-induced IL-18 binding protein was found to downregulate the Th17 response [11], and in several cases the induction of Th17 or IL-17 produc...

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