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

O'flynn, J. Dermot; Pol, Pieter van der; Dixon, Karen O.; Prohászka, Zoltán; Daha, Mohamed R.; Kooten, Cees van

doi:10.1152/ajprenal.00645.2014

Cited by 20 publications

(21 citation statements)

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“…This theory was later discounted and replaced with the well‐established role of properdin as a positive regulator of preexisting alternative pathway activity . Within the past decade, multiple studies have rediscovered the ability of properdin to act as an initiator of alternative pathway activity ( (Fig. ).…”

Section: Properdin As An Initiator Of Alternative Pathway Activity: Ementioning

confidence: 99%

“…While the physiological effects of the interactions between these molecules and properdin remain unknown, it is possible that they could account for the qualitative differences in binding observed for purified properdin vs properdin contained in serum. Recent evidence also indicates that monomeric C‐reactive protein (mCRP) inhibits the binding of unfractionated properdin to proximal tubular epithelial cells . Because mCRP is generated and present mainly on cell surfaces or local microenvironments, it is likely that the inhibitory capacity of mCRP may be limited to cell surfaces and not affect properdin activity in normal human serum.…”

Section: Properdin As An Initiator Of Alternative Pathway Activity: Ementioning

confidence: 99%

“…Aside from binding to key complement components in order to carry out their regulatory functions, both properdin and Factor H bind to a diverse set of ligands other than complement proteins. In addition to sulfatides and the polyanionic structures already mentioned, unfractionated properdin has recently been shown to bind to neutrophil myeloperoxidase, Factor H‐related protein‐5 (CFHR‐5)), and monomeric C‐reactive protein (mCRP) . Not only does Factor H bind mCRP, but myeloperoxidase has been shown to interfere with the interaction between mCRP and Factor H, and CFHR‐5 directly competes with Factor H for binding to pentraxin 3, thus limiting its function .…”

Section: Understanding the Interplay Between Properdin And Factor H Imentioning

confidence: 99%

“…Recent evidence also indicates that monomeric C-reactive protein (mCRP) inhibits the binding of unfractionated properdin to proximal tubular epithelial cells. 88 Because mCRP is generated and present mainly on cell surfaces or local microenvironments, 98 it is likely that the inhibitory capacity of mCRP may be limited to cell surfaces and not affect properdin activity in normal human serum. The ability of serum to inhibit direct properdin binding can also be influenced by the specific ligands, as Xu et al 91 showed that unfractionated properdin and properdin in either normal human serum or C3-depleted serum bound directly to necrotic cells to approximately the same extent.…”

Section: Properdin As An Initiator Of Alternative Pathway Activity:mentioning

confidence: 99%

“…In addition to sulfatides and the polyanionic structures already mentioned, unfractionated properdin has recently been shown to bind to neutrophil myeloperoxidase, 87 Factor H-related protein-5 (CFHR-5) 81 ), and monomeric C-reactive protein (mCRP). 88 Not only does Factor H bind mCRP, 188 but myeloperoxidase has been shown to interfere with the interaction between mCRP and Factor H, 189 Factor H also binds to many of the same polyanions associated with properdin binding, including heparin, 50,[191][192][193][194][195][196][197][198] heparan sulfate, 102,193,194,196 and chondroitin sulfate C. 26,199 Association with polyanions increases Factor H regulation on surfaces by directing it to specific cells 50,193 and inducing oligomerization via the C-terminal domains. 200 19-20.…”

Section: Understanding the Interplay Between Properdin And Factor Hmentioning

confidence: 99%

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Properdin: a tightly regulated critical inflammatory modulator

Blatt

Pathan

Ferreira

2016

Immunological Reviews

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SummaryThe complement alternative pathway is a powerful arm of the innate immune system that enhances diverse inflammatory responses in the human host. Key to the effects of the alternative pathway is properdin, a serum glycoprotein that can both initiate and positively regulate alternative pathway activity. Properdin is produced by many different leukocyte subsets and circulates as cyclic oligomers of monomeric subunits. While the formation of non‐physiological aggregates in purified properdin preparations and the presence of potential properdin inhibitors in serum have complicated studies of its function, properdin has, regardless, emerged as a key player in various inflammatory disease models. Here, we review basic properdin biology, emphasizing the major hurdles that have complicated the interpretation of results from properdin‐centered studies. In addition, we elaborate on an emerging role for properdin in thromboinflammation and discuss the potential utility of properdin inhibitors as long‐term therapeutic options to treat diseases marked by increased formation of platelet/granulocyte aggregates. Finally, we describe the interplay between properdin and the alternative pathway negative regulator, Factor H, and how aiming to understand these interactions can provide scientists with the most effective ways to manipulate alternative pathway activation in complex systems.

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Section: Properdin As An Initiator Of Alternative Pathway Activity: Ementioning

confidence: 99%

Section: Properdin As An Initiator Of Alternative Pathway Activity: Ementioning

confidence: 99%

Section: Understanding the Interplay Between Properdin And Factor H Imentioning

confidence: 99%

Section: Properdin As An Initiator Of Alternative Pathway Activity:mentioning

confidence: 99%

Section: Understanding the Interplay Between Properdin And Factor Hmentioning

confidence: 99%

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Properdin: a tightly regulated critical inflammatory modulator

Blatt

Pathan

Ferreira

2016

Immunological Reviews

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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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C-Reactive Protein and Its Structural Isoforms: An Evolutionary Conserved Marker and Central Player in Inflammatory Diseases and Beyond

McFadyen

Zeller

Potempa

et al. 2020

Subcellular Biochemistry

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

Abstract: O'Flynn J, van der Pol P, Dixon KO, Prohászka Z, Daha MR, van Kooten C. Monomeric C-reactive protein inhibits renal celldirected complement activation mediated by properdin. Am J Physiol

Cited by 20 publications

References 47 publications

Properdin: a tightly regulated critical inflammatory modulator

Properdin: a tightly regulated critical inflammatory modulator

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

C-Reactive Protein and Its Structural Isoforms: An Evolutionary Conserved Marker and Central Player in Inflammatory Diseases and Beyond

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