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Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity
Cell death and release of proinflammatory mediators contribute to mortality during sepsis. Specifically, caspase-11–dependent cell death contributes to pathology and decreases in survival time in sepsis models. Priming of the host cell, through TLR4 and interferon receptors, induces caspase-11 expre...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068231/ https://www.ncbi.nlm.nih.gov/pubmed/27697835 http://dx.doi.org/10.1084/jem.20160027 |
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author | Napier, Brooke A. Brubaker, Sky W. Sweeney, Timothy E. Monette, Patrick Rothmeier, Greggory H. Gertsvolf, Nina A. Puschnik, Andreas Carette, Jan E. Khatri, Purvesh Monack, Denise M. |
author_facet | Napier, Brooke A. Brubaker, Sky W. Sweeney, Timothy E. Monette, Patrick Rothmeier, Greggory H. Gertsvolf, Nina A. Puschnik, Andreas Carette, Jan E. Khatri, Purvesh Monack, Denise M. |
author_sort | Napier, Brooke A. |
collection | PubMed |
description | Cell death and release of proinflammatory mediators contribute to mortality during sepsis. Specifically, caspase-11–dependent cell death contributes to pathology and decreases in survival time in sepsis models. Priming of the host cell, through TLR4 and interferon receptors, induces caspase-11 expression, and cytosolic LPS directly stimulates caspase-11 activation, promoting the release of proinflammatory cytokines through pyroptosis and caspase-1 activation. Using a CRISPR-Cas9–mediated genome-wide screen, we identified novel mediators of caspase-11–dependent cell death. We found a complement-related peptidase, carboxypeptidase B1 (Cpb1), to be required for caspase-11 gene expression and subsequent caspase-11–dependent cell death. Cpb1 modifies a cleavage product of C3, which binds to and activates C3aR, and then modulates innate immune signaling. We find the Cpb1–C3–C3aR pathway induces caspase-11 expression through amplification of MAPK activity downstream of TLR4 and Ifnar activation, and mediates severity of LPS-induced sepsis (endotoxemia) and disease outcome in mice. We show C3aR is required for up-regulation of caspase-11 orthologues, caspase-4 and -5, in primary human macrophages during inflammation and that c3aR1 and caspase-5 transcripts are highly expressed in patients with severe sepsis; thus, suggesting that these pathways are important in human sepsis. Our results highlight a novel role for complement and the Cpb1–C3–C3aR pathway in proinflammatory signaling, caspase-11 cell death, and sepsis severity. |
format | Online Article Text |
id | pubmed-5068231 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-50682312017-04-17 Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity Napier, Brooke A. Brubaker, Sky W. Sweeney, Timothy E. Monette, Patrick Rothmeier, Greggory H. Gertsvolf, Nina A. Puschnik, Andreas Carette, Jan E. Khatri, Purvesh Monack, Denise M. J Exp Med Research Articles Cell death and release of proinflammatory mediators contribute to mortality during sepsis. Specifically, caspase-11–dependent cell death contributes to pathology and decreases in survival time in sepsis models. Priming of the host cell, through TLR4 and interferon receptors, induces caspase-11 expression, and cytosolic LPS directly stimulates caspase-11 activation, promoting the release of proinflammatory cytokines through pyroptosis and caspase-1 activation. Using a CRISPR-Cas9–mediated genome-wide screen, we identified novel mediators of caspase-11–dependent cell death. We found a complement-related peptidase, carboxypeptidase B1 (Cpb1), to be required for caspase-11 gene expression and subsequent caspase-11–dependent cell death. Cpb1 modifies a cleavage product of C3, which binds to and activates C3aR, and then modulates innate immune signaling. We find the Cpb1–C3–C3aR pathway induces caspase-11 expression through amplification of MAPK activity downstream of TLR4 and Ifnar activation, and mediates severity of LPS-induced sepsis (endotoxemia) and disease outcome in mice. We show C3aR is required for up-regulation of caspase-11 orthologues, caspase-4 and -5, in primary human macrophages during inflammation and that c3aR1 and caspase-5 transcripts are highly expressed in patients with severe sepsis; thus, suggesting that these pathways are important in human sepsis. Our results highlight a novel role for complement and the Cpb1–C3–C3aR pathway in proinflammatory signaling, caspase-11 cell death, and sepsis severity. The Rockefeller University Press 2016-10-17 /pmc/articles/PMC5068231/ /pubmed/27697835 http://dx.doi.org/10.1084/jem.20160027 Text en © 2016 Napier et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Napier, Brooke A. Brubaker, Sky W. Sweeney, Timothy E. Monette, Patrick Rothmeier, Greggory H. Gertsvolf, Nina A. Puschnik, Andreas Carette, Jan E. Khatri, Purvesh Monack, Denise M. Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity |
title | Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity |
title_full | Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity |
title_fullStr | Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity |
title_full_unstemmed | Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity |
title_short | Complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity |
title_sort | complement pathway amplifies caspase-11–dependent cell death and endotoxin-induced sepsis severity |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068231/ https://www.ncbi.nlm.nih.gov/pubmed/27697835 http://dx.doi.org/10.1084/jem.20160027 |
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