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Lack of Toll IL-1R8 Exacerbates Th17 Cell Responses in Fungal Infection¹

Silvia Bozza^*, Teresa Zelante^*, Silvia Moretti^*, Pierluigi Bonifazi^*, Antonella DeLuca^*, Carmen D’Angelo^*, Gloria Giovannini^*, Cecilia Garlanda, Louis Boon, Francesco Bistoni^*, Paolo Puccetti^*, Alberto Mantovani and Luigina Romani^2,*

^* Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy, and Fondazione "Istituto di Ricovero e Cura per le Biotecnologie Trapiantologiche" I.B.i.T., Perugia, Italy; Clinical Institute Humanitas, Istituti di Ricovero e Cura a Carattere Scientifico, Rozzano, Italy, and Institute of General Pathology, University of Milan, Milan, Italy; and Bioceros, Utrecht, The Netherlands

TLRs contribute to the inflammatory response in fungal infections. Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases. In this study, we tested the hypothesis that Toll IL-1R8 (TIR8)/single Ig IL-1-related receptor, a member of the IL-1R family acting as a negative regulator of TLR/IL-1R signaling, affects TLR responses in fungal infections. Genetically engineered Tir8^–/– mice were assessed for inflammatory and adaptive Th cell responses to Candida albicans and Aspergillus fumigatus. Inflammatory pathology and susceptibility to infection were higher in Tir8^–/– mice and were causally linked to the activation of the Th17 pathway. IL-1R signaling was involved in Th17 cell activation by IL-6 and TGF-β in that limited inflammatory pathology and relative absence of Th17 cell activation were observed in IL-1RI^–/– mice. These data demonstrate that TIR8 is required for host resistance to fungal infections and that it functions to negatively regulate IL-1-dependent activation of inflammatory Th17 responses. TIR8 may contribute toward fine-tuning the balance between protective immunity and immunopathology in infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by the National Research Project on AIDS, Contract 30G.28, "Opportunistic Infections and Tuberculosis," Italy, and by the Specific Targeted Research Project "EURAPS" (LSHM-CT-2005), Contract 005223 (FP6).

² Address correspondence and reprint requests to Dr. Luigina Romani, Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06126 Perugia, Italy. E-mail address: lromani{at}unipg.it

³ Abbreviations used in this paper: TIR8, Toll IL-1R8; DC, dendritic cell; MLN, mesenteric lymph node; MMP9, matrix metalloproteinase; MPO, myeloperoxidase; NOS₂, NO synthase; PMN, polymorphonuclear neutrophil; SIGIRR, single Ig IL-1-related receptor; TLN, thoracic lymph node; Treg, regulatory T cell.