PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis

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, Luigina Romani

Research output: Contribution to journalArticle

Abstract

The 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

Original languageEnglish
Pages (from-to)2340-2348
Number of pages9
JournalJournal of Immunology
Volume193
Issue number5
DOIs
Publication statusPublished - Sep 1 2014

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Fingerprint Dive into the research topics of 'PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis'. Together they form a unique fingerprint.

  • Cite this

    Bozza, S., Campo, S., Arseni, B., Inforzato, A., Ragnar, L., Bottazzi, B., Mantovani, A., Moretti, S., Oikonomous, V., De Santis, R., Carvalho, A., Salvatori, G., & Romani, L. (2014). PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis. Journal of Immunology, 193(5), 2340-2348. https://doi.org/10.4049/jimmunol.1400814