Ficolin-2 recognizes DNA and participates in the clearance of dying host cells

Jensen, Maria L.; Honoré, Christian; Hummelshøj, Tina; Hansen, Bo Moelholm; Madsen, Hans O.; Garred, Peter

doi:10.1016/j.molimm.2006.04.002

Cited by 128 publications

(124 citation statements)

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“…The ficolins primarily recognize acetylated compounds, such as GlcNAc and AcBSA, via their fibrinogen-like domain (18,19). Furthermore, ficolin-2 and ficolin-3 have been shown to bind a wide variety of exogenous and endogenous molecular patterns, including several strains of encapsulated Gram-positive bacteria (63,64), LPS from Gram- negative bacteria (65), DNA (22), mitochondria (66), and apoptotic cells (23). Ficolin-2 recognizes and binds ligands through four different binding groves with distinct binding properties (S1, S2, S3, and S4), giving ficolin-2 unusual recognition versatility.…”

Section: Discussionmentioning

confidence: 99%

“…Ficolins primarily recognize acetylated compounds via the fibrinogen-like domain, such as N-acetyl-D-glucosamine (GlcNAc) and acetylated BSA (AcBSA) (18,19). The LP recognition molecules have also been shown to recognize and participate in the removal of altered and dying host cells (20)(21)(22)(23). PRMs of the LP are found in complexes with the MBL/ficolin-associated serine proteases (MASPs).…”

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confidence: 99%

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Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Pilely

Rosbjerg

Genster

et al. 2016

The Journal of Immunology

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Cholesterol crystals (CC) play an essential role in the formation of atherosclerotic plaques. CC activate the classical and the alternative complement pathways, but the role of the lectin pathway is unknown. We hypothesized that the pattern recognition molecules (PRMs) from the lectin pathway bind CC and function as an upstream innate inflammatory signal in the pathophysiology of atherosclerosis. We investigated the binding of the PRMs mannose-binding lectin (MBL), ficolin-1, ficolin-2, and ficolin-3, the associated serine proteases, and complement activation products to CC in vitro using recombinant proteins, specific inhibitors, as well as deficient and normal sera. Additionally, we examined the deposition of ficolin-2 and MBL in human carotid plaques by immunohistochemistry and fluorescence microscopy. The results showed that the lectin pathway was activated on CC by binding of ficolin-2 and MBL in vitro, resulting in activation and deposition of complement activation products. MBL bound to CC in a calcium-dependent manner whereas ficolin-2 binding was calcium-independent. No binding was observed for ficolin-1 or ficolin-3. MBL and ficolin-2 were present in human carotid plaques, and binding of MBL to CC was confirmed in vivo by immunohistochemistry, showing localization of MBL around CC clefts. Moreover, we demonstrated that IgM, but not IgG, bound to CC in vitro and that C1q binding was facilitated by IgM. In conclusion, our study demonstrates that PRMs from the lectin pathway recognize CC and provides evidence for an important role for this pathway in the inflammatory response induced by CC in the pathophysiology of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Pilely

Rosbjerg

Genster

et al. 2016

The Journal of Immunology

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“…Common pathogen-associated molecular targets include lipoteichoic acids (LTA) and peptidoglycan (PG). l-ficolin therefore binds to Gram-positive bacteria such as Streptococcus and Staphylococcus species, but may also recognize certain lipopolysaccharides (LPS; Gram-negative bacteria), [10][11][12][13][14][15]. l-ficolin serum concentration varies between 1 and 12 mg/ml in healthy adults or children (with most values falling between 3 and 6 mg/ml) [16,17], but lower levels are found in cord blood samples ( [16]; our unpublished data).…”

Section: Introductionmentioning

confidence: 97%

Extremes of l-ficolin concentration in children with recurrent infections are associated with single nucleotide polymorphisms in the FCN2 gene

Cedzyński

Nuytinck

Atkinson

et al. 2007

Clinical and Experimental Immunology

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Summaryl-ficolin (also called ficolin-2, P35 or hucolin) is a soluble pattern recognition molecule of suspected importance in anti-microbial immunity. It activates the lectin pathway of complement and acts as an opsonin. l-ficolin, encoded by the FCN2 gene, recognizes microbial polysaccharides and glycoconjugates rich in GlcNAc or GalNAc. We report here data concerning four single nucleotide polymorphisms (SNPs) of the FCN2 gene and their relationship to l-ficolin serum concentrations. There are two pairs of SNPs in linkage disequilibrium: ss32469536 (located in promoter) with rs7851696 (in exon 8) and ss32469537 (promoter) with ss32469544 (exon 8). We selected groups possessing low or high serum l-ficolin concentrations (Յ 2·8 mg/ml or Ն 4·5 mg/ml, respectively) from Polish children suffering from recurrent respiratory infections (n = 146). Low l-ficolin levels were associated with variant alleles for ss32469536 and rs7851696 and normal alleles for ss32469537 and ss32469544. Conversely, high l-ficolin levels were associated with variant alleles of ss32469537 and ss32469544. FCN2 genotyping should be a valuable additional tool for disease association studies.

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“…By contrast, ficolin-3 has been reported to recognize only very few microbial ligands (14,15). Both ficolin-2 and ficolin-3 are capable of binding to apoptotic cells and increase phagocytosis of dying host cells (16,17).…”

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Ficolin-1–PTX3 Complex Formation Promotes Clearance of Altered Self-Cells and Modulates IL-8 Production

Jie

Doni

Romani

et al. 2013

The Journal of Immunology

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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.

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Ficolin-2 recognizes DNA and participates in the clearance of dying host cells

Cited by 128 publications

References 29 publications

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Extremes of l-ficolin concentration in children with recurrent infections are associated with single nucleotide polymorphisms in the FCN2 gene

Ficolin-1–PTX3 Complex Formation Promotes Clearance of Altered Self-Cells and Modulates IL-8 Production

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