TY - JOUR

T1 - Ficolin-1-PTX3 complex formation promotes clearance of altered self-cells and modulates IL-8 production

AU - Ma, Ying Jie

AU - Doni, Andrea

AU - Romani, Luigina

AU - Jürgensen, Henrik Jessen

AU - Behrendt, Niels

AU - Mantovani, Alberto

AU - Garred, Peter

PY - 2013/8/1

Y1 - 2013/8/1

N2 - The long pentraxin 3 (PTX3) has been shown to be important in maintaining internal tissue homeostasis and in protecting against fungal Aspergillus fumigatus infection. However, the molecular mechanisms of how these functions are elicited are poorly delineated. Ficolin-1 is a soluble pattern recognition molecule that interacts with PTX3. We hypothesized that heterocomplexes between ficolin-1 and PTX3 might mediate the signals necessary for sequestration of altered self-cells and A. fumigatus. We were able to show that ficolin-1 interacts with PTX3 via its fibrinogen-like domain. The interaction was affected in a pH- and divalent cation-sensitive manner. The primary binding site for ficolin-1 on PTX3 was located in the N-terminal domain portion of PTX3. Ficolin-1 and PTX3 heterocomplex formation occurred on dying host cells, but not on A. fumigatus. The heterocomplex formation was a prerequisite for enhancement of phagocytosis by human monocyte-derived macrophages and downregulation of IL-8 production during phagocytosis. On A. fumigatus, PTX3 exposed the C-terminal portion of the molecule, probably resulting in steric hindrance of ficolin-1 interaction with PTX3. These results demonstrate that ficolin-1 and PTX3 heterocomplex formation acts as a noninflammatory "find me and eat me" signal to sequester altered-host cells. The fact that the ficolin-1-PTX3 complex formation did not occur on A. fumigatus shows that PTX3 uses different molecular effector mechanisms, depending on which domains it exposes during ligand interaction.

AB - The long pentraxin 3 (PTX3) has been shown to be important in maintaining internal tissue homeostasis and in protecting against fungal Aspergillus fumigatus infection. However, the molecular mechanisms of how these functions are elicited are poorly delineated. Ficolin-1 is a soluble pattern recognition molecule that interacts with PTX3. We hypothesized that heterocomplexes between ficolin-1 and PTX3 might mediate the signals necessary for sequestration of altered self-cells and A. fumigatus. We were able to show that ficolin-1 interacts with PTX3 via its fibrinogen-like domain. The interaction was affected in a pH- and divalent cation-sensitive manner. The primary binding site for ficolin-1 on PTX3 was located in the N-terminal domain portion of PTX3. Ficolin-1 and PTX3 heterocomplex formation occurred on dying host cells, but not on A. fumigatus. The heterocomplex formation was a prerequisite for enhancement of phagocytosis by human monocyte-derived macrophages and downregulation of IL-8 production during phagocytosis. On A. fumigatus, PTX3 exposed the C-terminal portion of the molecule, probably resulting in steric hindrance of ficolin-1 interaction with PTX3. These results demonstrate that ficolin-1 and PTX3 heterocomplex formation acts as a noninflammatory "find me and eat me" signal to sequester altered-host cells. The fact that the ficolin-1-PTX3 complex formation did not occur on A. fumigatus shows that PTX3 uses different molecular effector mechanisms, depending on which domains it exposes during ligand interaction.

KW - Apoptosis

KW - Aspergillosis

KW - Aspergillus fumigatus

KW - Binding Sites

KW - C-Reactive Protein

KW - Cells, Cultured

KW - Humans

KW - Interleukin-8

KW - Lectins

KW - Leukocytes, Mononuclear

KW - Macrophages

KW - Phagocytosis

KW - Protein Binding

KW - Protein Interaction Domains and Motifs

KW - Protein Structure, Tertiary

KW - Serum Amyloid P-Component

KW - Signal Transduction

KW - Surface Plasmon Resonance

U2 - 10.4049/jimmunol.1300382

DO - 10.4049/jimmunol.1300382

M3 - Journal article

C2 - 23817411

VL - 191

SP - 1324

EP - 1333

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 3

ER -