Cargando…

Inhibition of the NLRP3/IL‐1β axis protects against sepsis‐induced cardiomyopathy

BACKGROUND: Septic cardiomyopathy worsens the prognosis of critically ill patients. Clinical data suggest that interleukin‐1β (IL‐1β), activated by the NLRP3 inflammasome, compromises cardiac function. Whether or not deleting Nlrp3 would prevent cardiac atrophy and improve diastolic cardiac function...

Descripción completa

Detalles Bibliográficos
Autores principales: Busch, Katharina, Kny, Melanie, Huang, Nora, Klassert, Tilman E., Stock, Magdalena, Hahn, Alexander, Graeger, Sebastian, Todiras, Mihail, Schmidt, Sibylle, Chamling, Bishwas, Willenbrock, Michael, Groß, Stefan, Biedenweg, Doreen, Heuser, Arnd, Scheidereit, Claus, Butter, Christian, Felix, Stephan B., Otto, Oliver, Luft, Friedrich C., Slevogt, Hortense, Fielitz, Jens
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718055/
https://www.ncbi.nlm.nih.gov/pubmed/34472725
http://dx.doi.org/10.1002/jcsm.12763
_version_ 1784624640722731008
author Busch, Katharina
Kny, Melanie
Huang, Nora
Klassert, Tilman E.
Stock, Magdalena
Hahn, Alexander
Graeger, Sebastian
Todiras, Mihail
Schmidt, Sibylle
Chamling, Bishwas
Willenbrock, Michael
Groß, Stefan
Biedenweg, Doreen
Heuser, Arnd
Scheidereit, Claus
Butter, Christian
Felix, Stephan B.
Otto, Oliver
Luft, Friedrich C.
Slevogt, Hortense
Fielitz, Jens
author_facet Busch, Katharina
Kny, Melanie
Huang, Nora
Klassert, Tilman E.
Stock, Magdalena
Hahn, Alexander
Graeger, Sebastian
Todiras, Mihail
Schmidt, Sibylle
Chamling, Bishwas
Willenbrock, Michael
Groß, Stefan
Biedenweg, Doreen
Heuser, Arnd
Scheidereit, Claus
Butter, Christian
Felix, Stephan B.
Otto, Oliver
Luft, Friedrich C.
Slevogt, Hortense
Fielitz, Jens
author_sort Busch, Katharina
collection PubMed
description BACKGROUND: Septic cardiomyopathy worsens the prognosis of critically ill patients. Clinical data suggest that interleukin‐1β (IL‐1β), activated by the NLRP3 inflammasome, compromises cardiac function. Whether or not deleting Nlrp3 would prevent cardiac atrophy and improve diastolic cardiac function in sepsis was unclear. Here, we investigated the role of NLRP3/IL‐1β in sepsis‐induced cardiomyopathy and cardiac atrophy. METHODS: Male Nlrp3 knockout (KO) and wild‐type (WT) mice were exposed to polymicrobial sepsis by caecal ligation and puncture (CLP) surgery (KO, n = 27; WT, n = 33) to induce septic cardiomyopathy. Sham‐treated mice served as controls (KO, n = 11; WT, n = 16). Heart weights and morphology, echocardiography and analyses of gene and protein expression were used to evaluate septic cardiomyopathy and cardiac atrophy. IL‐1β effects on primary and immortalized cardiomyocytes were investigated by morphological and molecular analyses. IonOptix and real‐time deformability cytometry (RT‐DC) analysis were used to investigate functional and mechanical effects of IL‐1β on cardiomyocytes. RESULTS: Heart morphology and echocardiography revealed preserved systolic (stroke volume: WT sham vs. WT CLP: 33.1 ± 7.2 μL vs. 24.6 ± 8.7 μL, P < 0.05; KO sham vs. KO CLP: 28.3 ± 8.1 μL vs. 29.9 ± 9.9 μL, n.s.; P < 0.05 vs. WT CLP) and diastolic (peak E wave velocity: WT sham vs. WT CLP: 750 ± 132 vs. 522 ± 200 mm/s, P < 0.001; KO sham vs. KO CLP: 709 ± 152 vs. 639 ± 165 mm/s, n.s.; P < 0.05 vs. WT CLP) cardiac function and attenuated cardiac (heart weight–tibia length ratio: WT CLP vs. WT sham: −26.6%, P < 0.05; KO CLP vs. KO sham: −3.3%, n.s.; P < 0.05 vs. WT CLP) and cardiomyocyte atrophy in KO mice during sepsis. IonOptix measurements showed that IL‐1β decreased contractility (cell shortening: IL‐1β: −15.4 ± 2.3%, P < 0.001 vs. vehicle, IL‐1RA: −6.1 ± 3.3%, P < 0.05 vs. IL‐1β) and relaxation of adult rat ventricular cardiomyocytes (time‐to‐50% relengthening: IL‐1β: 2071 ± 225 ms, P < 0.001 vs. vehicle, IL‐1RA: 564 ± 247 ms, P < 0.001 vs. IL‐1β), which was attenuated by an IL‐1 receptor antagonist (IL‐1RA). RT‐DC analysis indicated that IL‐1β reduced cardiomyocyte size (P < 0.001) and deformation (P < 0.05). RNA sequencing showed that genes involved in NF‐κB signalling, autophagy and lysosomal protein degradation were enriched in hearts of septic WT but not in septic KO mice. Western blotting and qPCR disclosed that IL‐1β activated NF‐κB and its target genes, caused atrophy and decreased myosin protein in myocytes, which was accompanied by an increased autophagy gene expression. These effects were attenuated by IL‐1RA. CONCLUSIONS: IL‐1β causes atrophy, impairs contractility and relaxation and decreases deformation of cardiomyocytes. Because NLRP3/IL‐1β pathway inhibition attenuates cardiac atrophy and cardiomyopathy in sepsis, it could be useful to prevent septic cardiomyopathy.
format Online
Article
Text
id pubmed-8718055
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-87180552022-01-06 Inhibition of the NLRP3/IL‐1β axis protects against sepsis‐induced cardiomyopathy Busch, Katharina Kny, Melanie Huang, Nora Klassert, Tilman E. Stock, Magdalena Hahn, Alexander Graeger, Sebastian Todiras, Mihail Schmidt, Sibylle Chamling, Bishwas Willenbrock, Michael Groß, Stefan Biedenweg, Doreen Heuser, Arnd Scheidereit, Claus Butter, Christian Felix, Stephan B. Otto, Oliver Luft, Friedrich C. Slevogt, Hortense Fielitz, Jens J Cachexia Sarcopenia Muscle Original Articles BACKGROUND: Septic cardiomyopathy worsens the prognosis of critically ill patients. Clinical data suggest that interleukin‐1β (IL‐1β), activated by the NLRP3 inflammasome, compromises cardiac function. Whether or not deleting Nlrp3 would prevent cardiac atrophy and improve diastolic cardiac function in sepsis was unclear. Here, we investigated the role of NLRP3/IL‐1β in sepsis‐induced cardiomyopathy and cardiac atrophy. METHODS: Male Nlrp3 knockout (KO) and wild‐type (WT) mice were exposed to polymicrobial sepsis by caecal ligation and puncture (CLP) surgery (KO, n = 27; WT, n = 33) to induce septic cardiomyopathy. Sham‐treated mice served as controls (KO, n = 11; WT, n = 16). Heart weights and morphology, echocardiography and analyses of gene and protein expression were used to evaluate septic cardiomyopathy and cardiac atrophy. IL‐1β effects on primary and immortalized cardiomyocytes were investigated by morphological and molecular analyses. IonOptix and real‐time deformability cytometry (RT‐DC) analysis were used to investigate functional and mechanical effects of IL‐1β on cardiomyocytes. RESULTS: Heart morphology and echocardiography revealed preserved systolic (stroke volume: WT sham vs. WT CLP: 33.1 ± 7.2 μL vs. 24.6 ± 8.7 μL, P < 0.05; KO sham vs. KO CLP: 28.3 ± 8.1 μL vs. 29.9 ± 9.9 μL, n.s.; P < 0.05 vs. WT CLP) and diastolic (peak E wave velocity: WT sham vs. WT CLP: 750 ± 132 vs. 522 ± 200 mm/s, P < 0.001; KO sham vs. KO CLP: 709 ± 152 vs. 639 ± 165 mm/s, n.s.; P < 0.05 vs. WT CLP) cardiac function and attenuated cardiac (heart weight–tibia length ratio: WT CLP vs. WT sham: −26.6%, P < 0.05; KO CLP vs. KO sham: −3.3%, n.s.; P < 0.05 vs. WT CLP) and cardiomyocyte atrophy in KO mice during sepsis. IonOptix measurements showed that IL‐1β decreased contractility (cell shortening: IL‐1β: −15.4 ± 2.3%, P < 0.001 vs. vehicle, IL‐1RA: −6.1 ± 3.3%, P < 0.05 vs. IL‐1β) and relaxation of adult rat ventricular cardiomyocytes (time‐to‐50% relengthening: IL‐1β: 2071 ± 225 ms, P < 0.001 vs. vehicle, IL‐1RA: 564 ± 247 ms, P < 0.001 vs. IL‐1β), which was attenuated by an IL‐1 receptor antagonist (IL‐1RA). RT‐DC analysis indicated that IL‐1β reduced cardiomyocyte size (P < 0.001) and deformation (P < 0.05). RNA sequencing showed that genes involved in NF‐κB signalling, autophagy and lysosomal protein degradation were enriched in hearts of septic WT but not in septic KO mice. Western blotting and qPCR disclosed that IL‐1β activated NF‐κB and its target genes, caused atrophy and decreased myosin protein in myocytes, which was accompanied by an increased autophagy gene expression. These effects were attenuated by IL‐1RA. CONCLUSIONS: IL‐1β causes atrophy, impairs contractility and relaxation and decreases deformation of cardiomyocytes. Because NLRP3/IL‐1β pathway inhibition attenuates cardiac atrophy and cardiomyopathy in sepsis, it could be useful to prevent septic cardiomyopathy. John Wiley and Sons Inc. 2021-09-02 2021-12 /pmc/articles/PMC8718055/ /pubmed/34472725 http://dx.doi.org/10.1002/jcsm.12763 Text en © 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Busch, Katharina
Kny, Melanie
Huang, Nora
Klassert, Tilman E.
Stock, Magdalena
Hahn, Alexander
Graeger, Sebastian
Todiras, Mihail
Schmidt, Sibylle
Chamling, Bishwas
Willenbrock, Michael
Groß, Stefan
Biedenweg, Doreen
Heuser, Arnd
Scheidereit, Claus
Butter, Christian
Felix, Stephan B.
Otto, Oliver
Luft, Friedrich C.
Slevogt, Hortense
Fielitz, Jens
Inhibition of the NLRP3/IL‐1β axis protects against sepsis‐induced cardiomyopathy
title Inhibition of the NLRP3/IL‐1β axis protects against sepsis‐induced cardiomyopathy
title_full Inhibition of the NLRP3/IL‐1β axis protects against sepsis‐induced cardiomyopathy
title_fullStr Inhibition of the NLRP3/IL‐1β axis protects against sepsis‐induced cardiomyopathy
title_full_unstemmed Inhibition of the NLRP3/IL‐1β axis protects against sepsis‐induced cardiomyopathy
title_short Inhibition of the NLRP3/IL‐1β axis protects against sepsis‐induced cardiomyopathy
title_sort inhibition of the nlrp3/il‐1β axis protects against sepsis‐induced cardiomyopathy
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718055/
https://www.ncbi.nlm.nih.gov/pubmed/34472725
http://dx.doi.org/10.1002/jcsm.12763
work_keys_str_mv AT buschkatharina inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT knymelanie inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT huangnora inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT klasserttilmane inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT stockmagdalena inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT hahnalexander inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT graegersebastian inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT todirasmihail inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT schmidtsibylle inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT chamlingbishwas inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT willenbrockmichael inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT großstefan inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT biedenwegdoreen inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT heuserarnd inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT scheidereitclaus inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT butterchristian inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT felixstephanb inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT ottooliver inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT luftfriedrichc inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT slevogthortense inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy
AT fielitzjens inhibitionofthenlrp3il1baxisprotectsagainstsepsisinducedcardiomyopathy