Factor H and Properdin Recognize Different Epitopes on Renal Tubular Epithelial Heparan Sulfate

Zaferani, Azadeh; Vivès, Romain R.; Pol, Pieter van der; Navis, Gerjan; Daha, Mohamed R.; Kooten, Cees van; Lortat‐Jacob, Hugues; Seelen, Marc A.; Born, Jacob van den

doi:10.1074/jbc.m112.380386

Cited by 46 publications

(67 citation statements)

References 51 publications

(60 reference statements)

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“…In contrast to our findings with exogenous ligands, previously shown with zymosan and E. coli (35) and in the present work with N. meningitidis, there is evidence of C3-independent properdin binding to ligands on endogenous cells, such as DNA on late apoptotic or necrotic cells (26), and presumably various glycosaminoglycans on early apoptotic T cells, but not necrotic T cells (25), activated platelets (27), and renal tubular epithelial cells (39,40). To the best of our knowledge, no data for endothelial cells and properdin binding have been reported previously, even though endothelial cells are a source of serum properdin and can express heparin sulfate proteoglycans, which have been shown to bind properdin (39,48).…”

Section: Discussioncontrasting

confidence: 56%

“…Properdin is significant in the defense against Neisseria species, and Neisseria gonorrhea was claimed to directly bind properdin (7), findings that have been extrapolated to N. meningitidis (37). Endothelial cells are a source of serum properdin (38), and properdin has been shown to interact with various glycosaminoglycans on endogenous cells (25,39,40).…”

Section: Discussionmentioning

confidence: 99%

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Properdin binding to complement activating surfaces depends on initial C3b deposition

Harboe

Johnson

Nymo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Two functions have been assigned to properdin; stabilization of the alternative convertase, C3bBb, is well accepted, whereas the role of properdin as pattern recognition molecule is controversial. The presence of nonphysiological aggregates in purified properdin preparations and experimental models that do not allow discrimination between the initial binding of properdin and binding secondary to C3b deposition is a critical factor contributing to this controversy. In previous work, by inhibiting C3, we showed that properdin binding to zymosan and Escherichia coli is not a primary event, but rather is solely dependent on initial C3 deposition. In the present study, we found that properdin in human serum bound dose-dependently to solid-phase myeloperoxidase. This binding was dependent on C3 activation, as demonstrated by the lack of binding in human serum with the C3-inhibitor compstatin Cp40, in C3-depleted human serum, or when purified properdin is applied in buffer. Similarly, binding of properdin to the surface of human umbilical vein endothelial cells or Neisseria meningitidis after incubation with human serum was completely C3-dependent, as detected by flow cytometry. Properdin, which lacks the structural homology shared by other complement pattern recognition molecules and has its major function in stabilizing the C3bBb convertase, was found to bind both exogenous and endogenous molecular patterns in a completely C3-dependent manner. We therefore challenge the view of properdin as a pattern recognition molecule, and argue that the experimental conditions used to test this hypothesis should be carefully considered, with emphasis on controlling initial C3 activation under physiological conditions.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Properdin binding to complement activating surfaces depends on initial C3b deposition

Harboe

Johnson

Nymo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, in patients with diabetic chronic kidney disease, biopsy analyses revealed tubular mCRP staining in the kidney, which is the same location observed for properdin staining in biopsies of proteinuric patients (14,39). These data are suggestive that mCRP may be allowed to interact with properdin; however, it could also possibly bind factor H (5, 28), a negative regulator of complement activation, which has also been shown to bind PTECs (47). This would be of interest to study in kidney disease patients with proteinuria, staining for the colocalization of factor H or properdin with mCRP to see how it relates to tubular injury.…”

Section: Discussionmentioning

confidence: 72%

“…Furthermore, mCRP has been shown to interact with other complement proteins, including C4bp, FH, and FHL-1 protein, indicating its diverse role in the complement system (5,26,28). The ability of mCRP to interact with FH and promote C3 inactivation is intriguing as both properdin and factor H bind heparin sulphates on PTECs (28,47). This may suggest a means by which mCRP can aid in regulating AP activation on PTECs, by interacting with FH and promoting C3 inactivation and inhibiting properdin-directed complement activation.…”

Section: Discussionmentioning

confidence: 99%

“…With previous findings demonstrating that AP activation occurred on PTECs, experiments in our laboratory by Gaarkeuken et al (14) demonstrated an integral role for properdin in mediating AP activation on PTECs, with deposition of properdin observed on the tubular luminal surface of biopsies from patients with proteinuric renal disease. Heparan sulphate on the surface of PTECs acted as a binding site for properdin, binding that can be inhibited by heparinoids (46,47). In addition, excretion of properdin in urine was associated with complement activation products and worse renal outcome in patients with at least 1 g/day of proteinuria in diabetic nephropathy and glomerular disease cases (40).…”

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confidence: 99%

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Monomeric C-reactive protein inhibits renal cell-directed complement activation mediated by properdin

O'flynn

Pol

Dixon

et al. 2016

American Journal of Physiology-Renal Physiology

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Initial properdin binding contributes to alternative pathway activation at the surface of viable and necrotic cells

et al. 2022

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Properdin, the only known positive regulator of the complement system, stabilizes the C3 convertase, thereby increasing its half-life. In contrast to most other complement factors, properdin is mainly produced extrahepatically by myeloid cells. Recent data suggest a role for properdin as a pattern recognition molecule. Here, we confirmed previous findings of properdin binding to different necrotic cells including Jurkat T cells. Binding can occur independent of C3, as demonstrated by HAP-1 C3 KO cells, excluding a role for endogenous C3. In view of the cellular source of properdin, interaction with myeloid cells was examined. Properdin bound to the surface of viable monocyte-derived pro-and anti-inflammatory macrophages, but not to DCs. Binding was demonstrated for purified properdin as well as fractionated P2, P3, and P4 properdin oligomers. Binding contributed to local complement activation as determined by C3 and C5b-9 deposition on the cell surfaces and seems a prerequisite for alternative pathway activation. Interaction of properdin with cell surfaces could be inhibited with the tick protein Salp20 and by different polysaccharides, depending on sulfation and chain length. These data identify properdin as a factor interacting with different cell surfaces, being either dead or alive, contributing to the local stimulation of complement activation. Keywords: Alternative pathway r Complement system r Dendritic cells r Macrophages r Properdin r Viable/death cells Grant support: The COMBAT consortium is sponsored by the Dutch Kidney Foundation (Grant 13OCA27).

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Factor H and Properdin Recognize Different Epitopes on Renal Tubular Epithelial Heparan Sulfate

Cited by 46 publications

References 51 publications

Properdin binding to complement activating surfaces depends on initial C3b deposition

Properdin binding to complement activating surfaces depends on initial C3b deposition

Monomeric C-reactive protein inhibits renal cell-directed complement activation mediated by properdin

Initial properdin binding contributes to alternative pathway activation at the surface of viable and necrotic cells

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