Endoplasmic reticulum aminopeptidase 2 regulates CD4 <sup>+</sup> T cells pyroptosis in rheumatoid arthritis

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Abstract

Objective

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease with a complex pathogenesis that has not yet been fully elucidated, and T-cell pyroptosis is an important pathogenetic factor in RA. This study aimed to investigate the role of endoplasmic reticulum aminopeptidase 2 (ERAP2) in the pyroptosis of CD4 ⁺ T cells in RA and the specific molecular mechanism.

Methods

Peripheral venous blood was collected from human subjects, and CD4 ⁺ T cells were isolated and activated to measure the level of pyroptosis and ERAP2 expression. Pyroptosis levels were assessed using immunofluorescence, flow cytometry, qRT-PCR, and Western blotting. Changes in pyroptosis levels were observed upon knockdown or overexpression of ERAP2. To detect activated Caspase-1 in tissues, chimeric mice were engrafted with human synovial tissue and reconstituted with human CD4 ⁺ T cells. CD4 + T cells were treated with GLI1 antagonists and SMO receptor agonists to detect changes in pyroptosis levels.

Results

CD4 ⁺ T cell levels undergoing pyroptosis were found to be elevated in the blood and synovium of RA patients. The gene and protein expression of ERAP2 were significantly higher in CD4 ⁺ T cells from RA patients. Deletion of ERAP2 suppressed pyroptosis of these cells, attenuated the activation of Caspase-1 in tissue T cells, and reduced tissue inflammatory responses. Reciprocally, overexpression of ERAP2 triggered inflammasome assembly, activated Caspase-1, and induced pyroptosis in CD4 ⁺ T cells. Mechanistically, ERAP2 inhibits the Hedgehog signaling pathway and upregulates the expression of nucleotide-binding oligomerization segment-like receptor family 3(NLRP3), cleaved Caspase-1, and Gasdermin D to promote pyroptosis in CD4 ⁺ T cells.

Conclusions

Taken together, our results identify a novel mechanism by which ERAP2 regulates RA development and document the effect of the ERAP2/Hedgehog signaling axis on pyroptosis of CD4 ⁺ T cells from RA patients.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13075-024-03271-3.

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Most cited references 34

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2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

Daniel Aletaha, Tuhina Neogi, Alan J Silman … (2010)

The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct "rheumatoid arthritis." In the new criteria set, classification as "definite RA" is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0-5), serologic abnormality (score range 0-3), elevated acute-phase response (score range 0-1), and symptom duration (2 levels; range 0-1). This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct "rheumatoid arthritis."

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Eukaryotic cells can initiate several distinct programmes of self-destruction, and the nature of the cell death process (non-inflammatory or proinflammatory) instructs responses of neighbouring cells, which in turn dictates important systemic physiological outcomes. Pyroptosis, or caspase 1-dependent cell death, is inherently inflammatory, is triggered by various pathological stimuli, such as stroke, heart attack or cancer, and is crucial for controlling microbial infections. Pathogens have evolved mechanisms to inhibit pyroptosis, enhancing their ability to persist and cause disease. Ultimately, there is a competition between host and pathogen to regulate pyroptosis, and the outcome dictates life or death of the host.

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Pyroptosis.

Lieselotte Vande Walle, Mohamed Lamkanfi (2016)

Injury and physical trauma may inflict accidental cell death, but we have come to realize during the past four decades that cells may also actively engage cell death when needed. These regulated cell death forms are intrinsically connected with human embryonic development, homeostatic maintenance and disease pathology. For instance, the human body is composed of approximately 10(14) cells, millions of which are removed daily by apoptosis and replaced with newly differentiated cells in order to secure organ functionality. Apoptotic cells are orderly packed in 'apoptotic bodies' for uptake by neighboring cells and professional phagocytes, thereby avoiding deleterious inflammatory responses by circulating leukocytes. Unlike apoptosis, however, more recently identified forms of regulated cell death - such as necroptosis and pyroptosis - are characterized by an early breach of the plasma membrane integrity, which results in extracellular spilling of the intracellular contents. Here, we will describe and discuss this and other features of pyroptosis.

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Author and article information

Contributors

Minhao Chen: chenminhao_nt@126.com

Hua Xu: xuhua1981111@126.com

Youhua Wang: wangyouhua99@163.com

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 25 January 2024

Publication date PMC-release: 25 January 2024

Publication date (Print): 2024

Volume: 26

Electronic Location Identifier: 36

Affiliations

GRID grid.440642.0, ISNI 0000 0004 0644 5481, Department of Orthopaedics, , Affiliated Hospital of Nantong University, ; Nantong, Jiangsu China

Article

Publisher ID: 3271

DOI: 10.1186/s13075-024-03271-3

PMC ID: 10810225

PubMed ID: 38273310

SO-VID: 52858205-976a-47d5-9bd0-9eb9edf773d9

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/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 29 July 2023

Date accepted : 14 January 2024

Funding

Funded by: National Natural Science Foundation of China

Award ID: 82072395

Award Recipient : Jianhua Zhang Hao Cai Weiwei Sun Weijie Wu Yunyi Nan Yingchen Ni Xinyuan Wu Minhao Chen Hua Xu Youhua Wang

Custom metadata

ScienceOpen disciplines: Orthopedics

Keywords: pyroptosis,cd4+ t cells,erap2,rheumatoid arthritis,hedgehog signaling pathway

Data availability:

ScienceOpen disciplines: Orthopedics

Keywords: pyroptosis, cd4+ t cells, erap2, rheumatoid arthritis, hedgehog signaling pathway

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