CircMAPK1 induces cell pyroptosis in sepsis-induced lung injury by mediating KDM2B mRNA decay to epigenetically regulate WNK1

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Abstract

Background

Macrophage pyroptosis is a pivotal inflammatory mechanism in sepsis-induced lung injury, however, the underlying mechanisms remain inadequately elucidated.

Methods

Lipopolysaccharides (LPS)/adenosine triphosphate (ATP)-stimulated macrophages and cecal ligation and puncture (CLP)-induced mouse model for sepsis were established. The levels of key molecules were examined by qRT-PCR, Western blotting, immunohistochemistry (IHC) and ELISA assay. The subcellular localization of circMAPK1 was detected by RNA fluorescence in situ hybridization (FISH). Cell viability, LDH release and caspase-1 activity were monitored by CCK-8, LDH assays, and flow cytometry. The bindings between KDM2B/H3K36me2 and WNK1 promoter was detected by chromatin immunoprecipitation (ChIP) assay and luciferase assay, and associations among circMAPK1, UPF1 and KDM2B mRNA were assessed by RNA pull-down or RNA immunoprecipitation (RIP) assays. The pathological injury of lung tissues was evaluated by lung wet/dry weight ratio and hematoxylin and eosin (H&E) staining.

Results

CircMAPK1 was elevated in patients with septic lung injury. Knockdown of circMAPK1 protected against LPS/ATP-impaired cell viability and macrophage pyroptosis via WNK1/NLRP3 axis. Mechanistically, loss of circMAPK1 enhanced the association between KDM2B and WNK1 promoter to promote the demethylation of WNK1 and increase its expression. CircMAPK1 facilitated KDM2B mRNA decay by recruiting UPF1. Functional experiments showed that silencing of KDM2B or WNK1 counteracted circMAPK1 knockdown-suppressed macrophage pyroptosis. In addition, silencing of circMAPK1 alleviated CLP-induced lung injury in mice via KDM2B/WNK1/NLRP3 axis.

Conclusion

CircMAPK1 exacerbates sepsis-induced lung injury by destabilizing KDM2B mRNA to suppress WNK1 expression, thus facilitating NLRP3-driven macrophage pyroptosis.

Supplementary Information

The online version contains supplementary material available at 10.1186/s10020-024-00932-6.

Related collections

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Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.

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Author and article information

Contributors

Xiaoran Liu:

ORCID: http://orcid.org/0000-0002-7245-8702

hy0203049@hainmc.edu.cn

Journal

Journal ID (nlm-ta): Mol Med

Journal ID (iso-abbrev): Mol Med

Title: Molecular Medicine

Publisher: BioMed Central (London )

ISSN (Print): 1076-1551

ISSN (Electronic): 1528-3658

Publication date (Electronic): 19 September 2024

Publication date PMC-release: 19 September 2024

Publication date Collection: 2024

Volume: 30

Electronic Location Identifier: 155

Affiliations

[1 ]Emergency Department of Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), ( https://ror.org/030sr2v21) Haikou, 570311 Hainan Province China

[2 ]Emergency trauma College of Hainan Medical University, ( https://ror.org/004eeze55) Haikou, 571199 Hainan Province China

[3 ]The First Affiliated Hospital of Hainan Medical College, Key Laboratory of Emergency and Trauma of Ministry of Education, ( https://ror.org/05wbpaf14) No.3 Xueyuan Road, Longhua District, Haikou, 571199 Hainan Province China

Author information

Xiaoran Liu http://orcid.org/0000-0002-7245-8702

Article

Publisher ID: 932

DOI: 10.1186/s10020-024-00932-6

PMC ID: 11414303

PubMed ID: 39300342

SO-VID: fc90f16f-8132-454f-9ac5-e5562f41ecfd

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 13 May 2024

Date accepted : 9 September 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82060357

Award Recipient : Xiaoran Liu

Custom metadata

Keywords: circmapk1,macrophage pyroptosis,sepsis,kdm2b,wnk1

Data availability:

Keywords: circmapk1, macrophage pyroptosis, sepsis, kdm2b, wnk1