A conformational change of C-reactive protein drives neutrophil extracellular trap formation in inflammation.

Felix M Bläsius, Steffen U Eisenhardt, Anke Schultze, Hendrik Feuerstein, David Braig, Oscar Winninger, Johannes Zeller, Lena Schütte, Ebru Karasu, Klemens Horst, Johannes Greven, Karlheinz Peter, Bettina Berger, Markus Huber-Lang, Rebecca Halbgebauer, Uwe Knippschild, Frank Hildebrand, David Alexander Christian Messerer

Journal: BMC biology 2025;23(1):4

PMID: 39773175

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Abstract

BACKGROUND

C-reactive protein (CRP) represents a routine diagnostic marker of inflammation. Dissociation of native pentameric CRP (pCRP) into the monomeric structure (mCRP) liberates proinflammatory features, presumably contributing to excessive immune cell activation via unknown molecular mechanisms.

RESULTS

In a multi-translational study of systemic inflammation, we found a time- and inflammation-dependent pCRP dissociation into mCRP. We were able to confirm that mCRP co-localizes with leukocytes at the site of injury after polytrauma and therefore assessed whether the CRP conformation potentiates neutrophil activation. We found mCRP-induced neutrophil-extracellular trap formation in vitro and ex vivo involving nicotinamide adenine dinucleotide phosphate oxidase activation, p38/mitogen-activated protein kinase signaling, and histone H3 citrullination. Mimicking the trauma milieu in a human ex vivo whole blood model, we found significant mCRP generation as well as NET formation, prevented by blocking pCRP conformational changes.

CONCLUSIONS

Our data provide novel molecular insights how CRP dissociation contributes to neutrophil activation as driver of various inflammatory disorders.

Address: Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Helmholtzstrasse 8/1, 89081, Ulm, Germany.; Department of Orthopedic Trauma Surgery, RWTH Aachen University, Aachen, Germany.; Department of Plastic and Hand Surgery, Medical Faculty of the University of Freiburg, University of Freiburg Medical Centre Freiburg, Freiburg, Germany.; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia.; Baker Heart and Diabetes Institute, Melbourne, Australia.; Department of General and Visceral Surgery, Ulm University Medical Center, 89081, Ulm, Germany.; Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Helmholtzstrasse 8/1, 89081, Ulm, Germany. [email protected].

DOI: 10.1186/s12915-024-02093-8

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https://assays.cancer.gov/CPTAC-1478

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https://antibodies.cancer.gov/detail/CPTC-CRP-1

MeSH Terms: Extracellular Traps, Humans, C-Reactive Protein, Inflammation, Neutrophils, Protein Conformation, Male, Neutrophil Activation