Role of the hedgehog signaling pathway in rheumatic diseases: An overview

Su, Yazhen; Xing, Hao; Kang, Jie; Bai, Linkun; Zhang, Liyun

doi:10.3389/fimmu.2022.940455

Cited by 4 publications

(2 citation statements)

References 100 publications

(109 reference statements)

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“…Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that involves inflammation of the synovial joints and causes the progressive destruction of cartilage and bone, leading to joint deformities [ 1 , 2 ]. The development of RA is influenced by multiple risk factors, including environmental and genetic variables, and is characterized by the production of excessive inflammatory mediators such as cytokines, chemokines, and autoantibodies associated with excessive activation of auto-reactive T and B cells which mediate autoimmune responses in the joints [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum aminopeptidase 2 regulates CD4+ T cells pyroptosis in rheumatoid arthritis

Zhang,

Cai,

Sun

et al. 2024

Arthritis Res Ther

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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.

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Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum aminopeptidase 2 regulates CD4+ T cells pyroptosis in rheumatoid arthritis

Zhang,

Cai,

Sun

et al. 2024

Arthritis Res Ther

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“… 12 Additionally, the Hedgehog signaling pathway was found to be aberrantly activated in rheumatic diseases such as RA, osteoarthritis, ankylosing spondylitis, and systemic sclerosis. 13 Considering these findings, inhibiting the Hedgehog signaling pathway may aid in the treatment of various cancers and inflammatory diseases. Nowadays, several small-molecule antagonists of SMO, such as vismodegib, sonidegib, and glasdegib, are approved by the Food and Drug Administration (FDA) to treat BCC and AML, respectively.…”

Section: Introductionmentioning

confidence: 99%