• Silvia Bozza, Silvia Campo, Brunilde Arseni, Antonio Inforzato, Lindstedt Ragnar, Barbara Bottazzi, Alberto Mantovani, Silvia Moretti, Vasileios Oikonomous, Rita De Santis, Agostinho Carvalho, Giovanni Salvatori, and Luigina Romani.
• Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy;
• J. Immunol. 2014 Sep 1;193(5):2340-8.

AbstractThe long pentraxin 3 (PTX3) modulates different effector pathways involved in innate resistance to Aspergillus fumigatus, including complement activation or promotion of phagocytosis by interacting with FcγRs. However, whether and how TLRs modulate PTX3 mediates antifungal resistance is not known. In this study, we demonstrate that PTX3 binds myeloid differentiation protein 2 (MD-2) in vitro and exerts its protective antifungal activity in vivo through TLR4/MD-2-mediated signaling. Similar to Tlr4(-/-) mice, Md2(-/-) mice displayed high susceptibility to pulmonary aspergillosis, a phenotype associated with a proinflammatory cytokine profile and impaired antifungal activity of polymorphonuclear neutrophils. Treating Md2(-/-) mice with PTX3 failed to confer immune protection against the fungus, whereas adoptive transfer of MD-2-competent polymorphonuclear neutrophils restored it. Mechanistically, engagement of MD-2 by PTX3-opsonized Aspergillus conidia activated the TLR4/Toll/IL-1R domain-containing adapter inducing IFN-β-dependent signaling pathway converging on IL-10. Thus, we have identified a novel receptor mechanism, involving the TLR4/MD-2/Toll/IL-1R domain-containing adapter inducing IFN-β-mediated signaling, whereby PTX3 elicits antifungal resistance with limited immunopathology in A. fumigatus infection.Copyright © 2014 by The American Association of Immunologists, Inc.

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