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C4b-binding protein...
C4b-binding protein inhibits particulate- and crystalline-induced NLRP3 inflammasome activation
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- Bierschenk, Damien (author)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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- Papac-Milicevic, Nikolina (author)
- Medical University of Vienna
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- Bresch, Ian P. (author)
- Hannover Medical School
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- Kovacic, Valentina (author)
- Medical University of Vienna
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- Bettoni, Serena (author)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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- Dziedzic, Mateusz (author)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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- Wetsel, Rick A. (author)
- University of Texas Health Science Center at Houston
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- Eschenburg, Susanne (author)
- Hannover Medical School
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- Binder, Christoph J. (author)
- Medical University of Vienna
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- Blom, Anna M. (author)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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- King, Ben C. (author)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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(creator_code:org_t)
- 2023
- 2023
- English.
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In: Frontiers in Immunology. - 1664-3224. ; 14
- Related links:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.3...
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Abstract
Subject headings
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- Dysregulated NLRP3 inflammasome activation drives a wide variety of diseases, while endogenous inhibition of this pathway is poorly characterised. The serum protein C4b-binding protein (C4BP) is a well-established inhibitor of complement with emerging functions as an endogenously expressed inhibitor of the NLRP3 inflammasome signalling pathway. Here, we identified that C4BP purified from human plasma is an inhibitor of crystalline- (monosodium urate, MSU) and particulate-induced (silica) NLRP3 inflammasome activation. Using a C4BP mutant panel, we identified that C4BP bound these particles via specific protein domains located on the C4BP α-chain. Plasma-purified C4BP was internalised into MSU- or silica-stimulated human primary macrophages, and inhibited MSU- or silica-induced inflammasome complex assembly and IL-1β cytokine secretion. While internalised C4BP in MSU or silica-stimulated human macrophages was in close proximity to the inflammasome adaptor protein ASC, C4BP had no direct effect on ASC polymerisation in in vitro assays. C4BP was also protective against MSU- and silica-induced lysosomal membrane damage. We further provide evidence for an anti-inflammatory function for C4BP in vivo, as C4bp-/- mice showed an elevated pro-inflammatory state following intraperitoneal delivery of MSU. Therefore, internalised C4BP is an inhibitor of crystal- or particle-induced inflammasome responses in human primary macrophages, while murine C4BP protects against an enhanced inflammatory state in vivo. Our data suggests C4BP has important functions in retaining tissue homeostasis in both human and mice as an endogenous serum inhibitor of particulate-stimulated inflammasome activation.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Keyword
- C4BP
- cytokine
- gout
- inflammasome
- MSU
- pyroptosis
- silica
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Bierschenk, Dami ...
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Papac-Milicevic, ...
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Bresch, Ian P.
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Kovacic, Valenti ...
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Bettoni, Serena
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Dziedzic, Mateus ...
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Wetsel, Rick A.
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Eschenburg, Susa ...
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Binder, Christop ...
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Blom, Anna M.
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King, Ben C.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
- Articles in the publication
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Frontiers in Imm ...
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Lund University