PTX3 Binds MD-2 and Promotes TRIF-Dependent Immune Protection in Aspergillosis

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.

Impaired calcineurin signaling in myeloid cells results in downregulation of pentraxin-3 and increased susceptibility to aspergillosis

“…38 Ptx3 is known to exert a broad range of immune activities from opsonic capacity 24 to complement activation and phagocytosis, 30 and stimulation of the TLR4-MD-2 pathway. 39 During fungal infections, Ptx3 expression is activated in DCs through TLR activation and NF-kB, 39,40 and it also forms a component of the neutrophil extracellular traps protein pool. 41 Here, we report that Ptx3 expression can be co-regulated through the calcineurin-NFAT pathway, suggesting that systemically administered immunosuppressive drugs targeting the calcineurin-NFAT binding might affect Ptx3 production.…”

Innate Lung Defense during Invasive Aspergillosis: New Mechanisms

“…As detailed earlier, TLR4 is recognized as an important PRR in IA defense. PTX3 was recently identified as binding to myeloid differentiation protein 2 (MD-2) in vitro and mediating antifungal activity in vivo via TLR4/MD-2-mediated signaling [39] ; mechanistically, the engagement of MD-2 by PTX3-opsonized A. fumigatus activated a TRIFmediated IFN-β-dependent signaling pathway. Immunosuppression with drugs such as cyclosporine A or tacrolimus is commonly associated with a higher incidence of IA.…”

Immunity against fungi

“…Fungal ligands activate TLR1-4, TLR-6, TLR-9, and NOD2 signaling in a variety of cell types (5,9). For example, PTX3-opsonized A. fumigatus conidia activate TLR-4/MD-2/TRIF-dependent signaling that mediates IL-10 production (62). Following internalization, A. fumigatus conidia trigger macrophage TLR-9-, calcineurin-, and BTK-dependent TNF release (63); however, humans with NLR or TLR/MyD88 signaling defects do not manifest with fungal infections (64,65).…”