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Damping Excessive Inflammation and Tissue Damage in Mycobacterium tuberculosis Infection by Toll IL-1 Receptor 8/Single Ig IL-1-Related Receptor, a Negative Regulator of IL-1/TLR Signaling¹

Cecilia Garlanda, Diana Di Liberto^*, Annunciata Vecchi, Marco P. La Manna^*, Chiara Buracchi, Nadia Caccamo^*, Alfredo Salerno^*, Francesco Dieli^2,3,* and Alberto Mantovani^2,

^* Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Palermo, Italy; Istituto Clinico Humanitas, Istituti di Ricovero e Cura a Carattere Scientifico, Rozzano, Italy, and Istituto di Patologia Generale, Università di Milano, Milan, Italy

Toll IL-1R 8/single Ig IL-1-related receptor (TIR8/SIGIRR) is a member of the IL-1R family, expressed by epithelial tissues and immature dendritic cells, and is regarded as a negative regulator of TLR/IL-1R signaling. Tir8-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis, despite controlling efficiently the number of viable bacilli in different organs. Tir8^–/–-infected mice showed an increased number of neutrophils and macrophages in the lungs; however, mycobacteria-specific CD4 and CD8 T cells were similar in Tir8^–/– and Tir8^+/+ mice. Exaggerated mortality of Tir8^–/– mice was due to massive liver necrosis and was accompanied by increased levels of IL-1β and TNF- in lung mononuclear cells and serum, as well as by increased production of IL-1β and TNF- by M. tuberculosis-infected dendritic cells in vitro. Accordingly, blocking IL-1β and TNF- with a mix of anti-cytokine Abs, significantly prolonged survival of Tir8^–/– mice. Thus, TIR8/SIGIRR plays a key role in damping inflammation and tissue damage in M. tuberculosis 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 was supported by the Commission of the European Communities, by Contracts LSHP-CT-2003-503240, Mucosal Vaccines for Poverty-Related Diseases, and LSHB-CT-2005-005203, MUGEN, from the European Union Sixth Framework Programme, the University of Palermo, Fondazione Telethon, and Fondazione Cariplo (Progetto NOBEL).

² A.M. and F.D. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Francesco Dieli, Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Corso Tukory 211, 90134 Palermo, Italy. E-mail address: dieli{at}unipa.it

⁴ Abbreviations used in this paper: DC, dendritic cell; BCG, bacillus Calmette-Guérin; TIR, Toll/IL-1R; SIGIRR, single Ig IL-1-related receptor; MOI, multiplicity of infection.

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