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Exogenous Pentraxin 3 Restores Antifungal Resistance and Restrains Inflammation in Murine Chronic Granulomatous Disease¹

Carmen D'Angelo^*, Antonella De Luca^*, Teresa Zelante^*, Pierluigi Bonifazi^*, Silvia Moretti^*, Gloria Giovannini^*, Rossana Giulietta Iannitti^*, Silvia Zagarella^*, Silvia Bozza^*, Silvia Campo, Giovanni Salvatori and Luigina Romani^2,*

^* Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy and Sigma-Tau, Pomezia, Rome, Italy

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening bacterial and fungal infections and hyperinflammation. The susceptibility to aspergillosis in experimental CGD (p47^phox–/– mice) is associated with the failure to control the inherent inflammatory response to the fungus and to restrict the activation of inflammatory Th17 cells. We assessed whether pentraxin (PTX)3, a member of a family of multimeric pattern-recognition proteins with potent anti-Aspergillus activity, could limit pathogenic inflammation in p47^phox–/– mice by curbing the IL–23/Th17 inflammatory axis in response to the fungus. We found that the production of PTX3 was delayed in CGD mice in infection but exogenous administration of PTX3 early in infection restored antifungal resistance and restrained the inflammatory response to the fungus. This occurred through down-regulation of IL-23 production by dendritic cells and epithelial cells which resulted in limited expansion of IL-23R^{+ +} T cells producing IL-17A and the emergence of Th1/Treg responses with minimum pathology. Thus, PTX3 could be therapeutically used for the exploitation of NADPH-independent mechanism(s) of antifungal immune protection with limited immunopathology in CGD.

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 work was supported by the Chronic Granulomatous Disorder Research Trust (Grant Number J4G/06/05).

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, Perugia, Italy. E-mail address: lromani{at}unipg.it

³ Abbreviations used in this paper: CGD, chronic granulomatous disease; Treg, regulatory T cell; PTX3, pentraxin 3; WT, wild type; i.n., intranasal; i.t., intratracheal; BAL, bronchoalveolar lavage; DC, dendritic cell; TLN, thoracic lymph node; ROI, reactive oxygen intermediate; PMN, polymorphonuclear neutrophil.