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Cystatin C deficiency increases LPS-induced sepsis and NLRP3 inflammasome activation in mice
ID Biasizzo, Monika (Author), ID Trstenjak-Prebanda, Mojca (Author), ID Dolinar, Klemen (Author), ID Pirkmajer, Sergej (Author), ID Završnik, Janja (Author), ID Turk, Boris (Author), ID Kopitar-Jerala, Nataša (Author)

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Abstract
Cystatin C is a potent cysteine protease inhibitor that plays an important role in various biological processes including cancer, cardiovascular diseases and neurodegenerative diseases. However, the role of CstC in inflammation is still unclear. In this study we demonstrated that cystatin C-deficient mice were significantly more sensitive to the lethal LPS-induced sepsis. We further showed increased caspase-11 gene expression and enhanced processing of pro-inflammatory cytokines IL-1β and IL-18 in CstC KO bone marrow-derived macrophages (BMDM) upon LPS and ATP stimulation. Pre-treatment of BMDMs with the cysteine cathepsin inhibitor E-64d did not reverse the effect of CstC deficiency on IL-1β processing and secretion, suggesting that the increased cysteine cathepsin activity determined in CstC KO BMDMs is not essential for NLRP3 inflammasome activation. The CstC deficiency had no effect on (mitochondrial) reactive oxygen species (ROS) generation, the MAPK signaling pathway or the secretion of anti-inflammatory cytokine IL-10. However, CstC-deficient BMDMs showed dysfunctional autophagy, as autophagy induction via mTOR and AMPK signaling pathways was suppressed and accumulation of SQSTM1/p62 indicated a reduced autophagic flux. Collectively, our study demonstrates that the excessive inflammatory response to the LPS-induced sepsis in CstC KO mice is dependent on increased caspase-11 expression and impaired autophagy, but is not associated with increased cysteine cathepsin activity.

Language:English
Keywords:cystatin C, lipopolysaccharide, NLRP3 inflammasome, autophagy, cysteine proteases, interleukin-1 (IL-1)
Work type:Article
Typology:1.01 - Original Scientific Article
Organization:MF - Faculty of Medicine
FKKT - Faculty of Chemistry and Chemical Technology
Publication status:Published
Publication version:Version of Record
Year:2021
Number of pages:18 str.
Numbering:Vol. 10, iss. 8, art. 2071
PID:20.500.12556/RUL-135985 This link opens in a new window
UDC:616-092
ISSN on article:2073-4409
DOI:10.3390/cells10082071 This link opens in a new window
COBISS.SI-ID:72910851 This link opens in a new window
Publication date in RUL:05.04.2022
Views:552
Downloads:110
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Record is a part of a journal

Title:Cells
Shortened title:Cells
Publisher:MDPI
ISSN:2073-4409
COBISS.SI-ID:519958809 This link opens in a new window

Licences

License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:12.08.2021

Secondary language

Language:Slovenian
Keywords:cistatin C, lipopolisaharid, vnetni virus NLRP3

Projects

Funder:ARRS - Slovenian Research Agency
Project number:P1-0140
Name:Proteoliza in njena regulacija

Funder:ARRS - Slovenian Research Agency
Funding programme:Young researchers

Funder:ARRS - Slovenian Research Agency
Project number:P3-0043
Name:Molekularni mehanizmi razvoja in delovanja skeletne mišice

Funder:ARRS - Slovenian Research Agency
Project number:J7-8276
Name:Vpliv protirevmatičnih zdravil na inzulinsko rezistenco in energijsko presnovo v skeletni mišici

Funder:Other - Other funder or multiple funders
Funding programme:COST
Project number:CA15203
Name:Evolution-Age-Gender-Lifestyle-Environment: mitochondrial fitness mapping
Acronym:MitoEAGLE

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