Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites

David Braig, Tracy L. Nero, Hans Georg Koch, Benedict Kaiser, Xiaowei Wang, Jan R. Thiele, Craig J. Morton, Johannes Zeller, Jurij Kiefer, Lawrence A. Potempa, Natalie A. Mellett, Luke A. Miles, Xiao Jun Du, Peter J. Meikle, Markus Huber-Lang, G. Björn Stark, Michael W. Parker, Karlheinz Peter, Steffen U. Eisenhardt

Research output: Contribution to journalArticleResearchpeer-review

Abstract

C-reactive protein (CRP) concentrations rise in response to tissue injury or infection. Circulating pentameric CRP (pCRP) localizes to damaged tissue where it leads to complement activation and further tissue damage. In-depth knowledge of the pCRP activation mechanism is essential to develop therapeutic strategies to minimize tissue injury. Here we demonstrate that pCRP by binding to cell-derived microvesicles undergoes a structural change without disrupting the pentameric symmetry (pCRP∗). pCRP∗ constitutes the major CRP species in human-inflamed tissue and allows binding of complement factor 1q (C1q) and activation of the classical complement pathway. pCRP∗-microvesicle complexes lead to enhanced recruitment of leukocytes to inflamed tissue. A small-molecule inhibitor of pCRP (1,6-bis(phosphocholine)-hexane), which blocks the pCRP-microvesicle interactions, abrogates these proinflammatory effects. Reducing inflammation-mediated tissue injury by therapeutic inhibition might improve the outcome of myocardial infarction, stroke and other inflammatory conditions.

Original languageEnglish
Article number14188
Number of pages19
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 23 Jan 2017

Cite this

Braig, D., Nero, T. L., Koch, H. G., Kaiser, B., Wang, X., Thiele, J. R., ... Eisenhardt, S. U. (2017). Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites. Nature Communications, 8, [14188]. https://doi.org/10.1038/ncomms14188
Braig, David ; Nero, Tracy L. ; Koch, Hans Georg ; Kaiser, Benedict ; Wang, Xiaowei ; Thiele, Jan R. ; Morton, Craig J. ; Zeller, Johannes ; Kiefer, Jurij ; Potempa, Lawrence A. ; Mellett, Natalie A. ; Miles, Luke A. ; Du, Xiao Jun ; Meikle, Peter J. ; Huber-Lang, Markus ; Stark, G. Björn ; Parker, Michael W. ; Peter, Karlheinz ; Eisenhardt, Steffen U. / Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites. In: Nature Communications. 2017 ; Vol. 8.
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title = "Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites",
abstract = "C-reactive protein (CRP) concentrations rise in response to tissue injury or infection. Circulating pentameric CRP (pCRP) localizes to damaged tissue where it leads to complement activation and further tissue damage. In-depth knowledge of the pCRP activation mechanism is essential to develop therapeutic strategies to minimize tissue injury. Here we demonstrate that pCRP by binding to cell-derived microvesicles undergoes a structural change without disrupting the pentameric symmetry (pCRP∗). pCRP∗ constitutes the major CRP species in human-inflamed tissue and allows binding of complement factor 1q (C1q) and activation of the classical complement pathway. pCRP∗-microvesicle complexes lead to enhanced recruitment of leukocytes to inflamed tissue. A small-molecule inhibitor of pCRP (1,6-bis(phosphocholine)-hexane), which blocks the pCRP-microvesicle interactions, abrogates these proinflammatory effects. Reducing inflammation-mediated tissue injury by therapeutic inhibition might improve the outcome of myocardial infarction, stroke and other inflammatory conditions.",
author = "David Braig and Nero, {Tracy L.} and Koch, {Hans Georg} and Benedict Kaiser and Xiaowei Wang and Thiele, {Jan R.} and Morton, {Craig J.} and Johannes Zeller and Jurij Kiefer and Potempa, {Lawrence A.} and Mellett, {Natalie A.} and Miles, {Luke A.} and Du, {Xiao Jun} and Meikle, {Peter J.} and Markus Huber-Lang and Stark, {G. Bj{\"o}rn} and Parker, {Michael W.} and Karlheinz Peter and Eisenhardt, {Steffen U.}",
year = "2017",
month = "1",
day = "23",
doi = "10.1038/ncomms14188",
language = "English",
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journal = "Nature Communications",
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Braig, D, Nero, TL, Koch, HG, Kaiser, B, Wang, X, Thiele, JR, Morton, CJ, Zeller, J, Kiefer, J, Potempa, LA, Mellett, NA, Miles, LA, Du, XJ, Meikle, PJ, Huber-Lang, M, Stark, GB, Parker, MW, Peter, K & Eisenhardt, SU 2017, 'Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites' Nature Communications, vol. 8, 14188. https://doi.org/10.1038/ncomms14188

Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites. / Braig, David; Nero, Tracy L.; Koch, Hans Georg; Kaiser, Benedict; Wang, Xiaowei; Thiele, Jan R.; Morton, Craig J.; Zeller, Johannes; Kiefer, Jurij; Potempa, Lawrence A.; Mellett, Natalie A.; Miles, Luke A.; Du, Xiao Jun; Meikle, Peter J.; Huber-Lang, Markus; Stark, G. Björn; Parker, Michael W.; Peter, Karlheinz; Eisenhardt, Steffen U.

In: Nature Communications, Vol. 8, 14188, 23.01.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites

AU - Braig, David

AU - Nero, Tracy L.

AU - Koch, Hans Georg

AU - Kaiser, Benedict

AU - Wang, Xiaowei

AU - Thiele, Jan R.

AU - Morton, Craig J.

AU - Zeller, Johannes

AU - Kiefer, Jurij

AU - Potempa, Lawrence A.

AU - Mellett, Natalie A.

AU - Miles, Luke A.

AU - Du, Xiao Jun

AU - Meikle, Peter J.

AU - Huber-Lang, Markus

AU - Stark, G. Björn

AU - Parker, Michael W.

AU - Peter, Karlheinz

AU - Eisenhardt, Steffen U.

PY - 2017/1/23

Y1 - 2017/1/23

N2 - C-reactive protein (CRP) concentrations rise in response to tissue injury or infection. Circulating pentameric CRP (pCRP) localizes to damaged tissue where it leads to complement activation and further tissue damage. In-depth knowledge of the pCRP activation mechanism is essential to develop therapeutic strategies to minimize tissue injury. Here we demonstrate that pCRP by binding to cell-derived microvesicles undergoes a structural change without disrupting the pentameric symmetry (pCRP∗). pCRP∗ constitutes the major CRP species in human-inflamed tissue and allows binding of complement factor 1q (C1q) and activation of the classical complement pathway. pCRP∗-microvesicle complexes lead to enhanced recruitment of leukocytes to inflamed tissue. A small-molecule inhibitor of pCRP (1,6-bis(phosphocholine)-hexane), which blocks the pCRP-microvesicle interactions, abrogates these proinflammatory effects. Reducing inflammation-mediated tissue injury by therapeutic inhibition might improve the outcome of myocardial infarction, stroke and other inflammatory conditions.

AB - C-reactive protein (CRP) concentrations rise in response to tissue injury or infection. Circulating pentameric CRP (pCRP) localizes to damaged tissue where it leads to complement activation and further tissue damage. In-depth knowledge of the pCRP activation mechanism is essential to develop therapeutic strategies to minimize tissue injury. Here we demonstrate that pCRP by binding to cell-derived microvesicles undergoes a structural change without disrupting the pentameric symmetry (pCRP∗). pCRP∗ constitutes the major CRP species in human-inflamed tissue and allows binding of complement factor 1q (C1q) and activation of the classical complement pathway. pCRP∗-microvesicle complexes lead to enhanced recruitment of leukocytes to inflamed tissue. A small-molecule inhibitor of pCRP (1,6-bis(phosphocholine)-hexane), which blocks the pCRP-microvesicle interactions, abrogates these proinflammatory effects. Reducing inflammation-mediated tissue injury by therapeutic inhibition might improve the outcome of myocardial infarction, stroke and other inflammatory conditions.

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U2 - 10.1038/ncomms14188

DO - 10.1038/ncomms14188

M3 - Article

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 14188

ER -