Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

Jitka Petrlova; Finja C Hansen; Mariena J A van der Plas; Roland G Huber; Matthias Mörgelin; Martin Malmsten; Peter J Bond; Artur Schmidtchen

doi:10.1073/pnas.1619609114

Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

Jitka Petrlova, Finja C Hansen, Mariena J A van der Plas, Roland G Huber, Matthias Mörgelin, Martin Malmsten, Peter J Bond, Artur Schmidtchen

30 Citations (Scopus)

Abstract

Effective control of endotoxins and bacteria is crucial for normal wound healing. During injury, the key enzyme thrombin is formed, leading to generation of fibrin. Here, we show that human neutrophil elastase cleaves thrombin, generating 11-kDa thrombin-derived C-terminal peptides (TCPs), which bind to and form amorphous amyloid-like aggregates with both bacterial lipopolysaccharide (LPS) and gram-negative bacteria. In silico molecular modeling using atomic resolution and coarse-grained simulations corroborates our experimental observations, altogether indicating increased aggregation through LPS-mediated intermolecular contacts between clusters of TCP molecules. Upon bacterial aggregation, recombinantly produced TCPs induce permeabilization of Escherichia coli and phagocytic uptake. TCPs of about 11 kDa are present in acute wound fluids as well as in fibrin sloughs from patients with infected wounds. We noted aggregation and colocalization of LPS with TCPs in such fibrin material, which indicates the presence of TCP-LPS aggregates under physiological conditions. Apart from identifying a function of proteolyzed thrombin and its fragments, our findings provide an interesting link between the coagulation system, innate immunity, LPS scavenging, and protein aggregation/amyloid formation.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	21
Pages (from-to)	E4213-E4222
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1619609114
Publication status	Published - 23 May 2017

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Journal Article

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Petrlova, J., Hansen, F. C., van der Plas, M. J. A., Huber, R. G., Mörgelin, M., Malmsten, M., Bond, P. J., & Schmidtchen, A. (2017). Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism. Proceedings of the National Academy of Sciences of the United States of America, 114(21), E4213-E4222. https://doi.org/10.1073/pnas.1619609114

Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism. / Petrlova, Jitka; Hansen, Finja C; van der Plas, Mariena J A et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 21, 23.05.2017, p. E4213-E4222.

Research output: Contribution to journal › Journal article › Research › peer-review

Petrlova, J, Hansen, FC, van der Plas, MJA, Huber, RG, Mörgelin, M, Malmsten, M, Bond, PJ & Schmidtchen, A 2017, 'Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 21, pp. E4213-E4222. https://doi.org/10.1073/pnas.1619609114

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AB - Effective control of endotoxins and bacteria is crucial for normal wound healing. During injury, the key enzyme thrombin is formed, leading to generation of fibrin. Here, we show that human neutrophil elastase cleaves thrombin, generating 11-kDa thrombin-derived C-terminal peptides (TCPs), which bind to and form amorphous amyloid-like aggregates with both bacterial lipopolysaccharide (LPS) and gram-negative bacteria. In silico molecular modeling using atomic resolution and coarse-grained simulations corroborates our experimental observations, altogether indicating increased aggregation through LPS-mediated intermolecular contacts between clusters of TCP molecules. Upon bacterial aggregation, recombinantly produced TCPs induce permeabilization of Escherichia coli and phagocytic uptake. TCPs of about 11 kDa are present in acute wound fluids as well as in fibrin sloughs from patients with infected wounds. We noted aggregation and colocalization of LPS with TCPs in such fibrin material, which indicates the presence of TCP-LPS aggregates under physiological conditions. Apart from identifying a function of proteolyzed thrombin and its fragments, our findings provide an interesting link between the coagulation system, innate immunity, LPS scavenging, and protein aggregation/amyloid formation.

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Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

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