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Promoter Methylation Leads to Decreased ZFP36 Expression and Deregulated NLRP3 Inflammasome Activation in Psoriatic Fibroblasts.

ABSTRACT: The mRNA-destabilizing protein tristetraprolin (TTP), encoded by the ZFP36 gene, is known to be able to end inflammatory responses by directly targeting and destabilizing mRNAs encoding pro-inflammatory cytokines. We analyzed its role in psoriasis, a disease characterized by chronic inflammation. We observed that TTP is downregulated in fibroblasts deriving from psoriasis patients compared to those deriving from healthy individuals and that psoriatic fibroblasts exhibit abnormal inflammasome activity compared to their physiological counterpart. This phenomenon depends on TTP downregulation. In fact, following restoration, TTP is capable of directly targeting for degradation NLRP3 mRNA, thereby drastically decreasing inflammasome activation. Moreover, we provide evidence that ZFP36 undergoes methylation in psoriasis, by virtue of the presence of long stretches of CpG dinucleotides both in the promoter and the coding region. Besides confirming that a perturbation of TTP expression might underlie the pathogenesis of psoriasis, we suggest that deregulated inflammasome activity might play a role in the disease alongside deregulated cytokine expression.

SUBMITTER: Bertesi M

PROVIDER: S-EPMC7874095 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Promoter Methylation Leads to Decreased <i>ZFP36</i> Expression and Deregulated NLRP3 Inflammasome Activation in Psoriatic Fibroblasts.

Bertesi Matteo M Fantini Sebastian S Alecci Claudia C Lotti Roberta R Martello Andrea A Parenti Sandra S Carretta Chiara C Marconi Alessandra A Grande Alexis A Pincelli Carlo C Zanocco-Marani Tommaso T

Frontiers in medicine 20210122

The mRNA-destabilizing protein tristetraprolin (TTP), encoded by the <i>ZFP36</i> gene, is known to be able to end inflammatory responses by directly targeting and destabilizing mRNAs encoding pro-inflammatory cytokines. We analyzed its role in psoriasis, a disease characterized by chronic inflammation. We observed that TTP is downregulated in fibroblasts deriving from psoriasis patients compared to those deriving from healthy individuals and that psoriatic fibroblasts exhibit abnormal inflammas ...[more]

PMID: 33585499

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Project description:INTRODUCTION:Osteoarthritis (OA) is an inflammatory disease of the joints that causes progressive disability in the elderly. Reactive oxygen species (ROS) play an important role in OA development; they may activate the NLRP3 inflammasome, thereby inducing the secretion of proinflammatory IL-1? and IL-18, leading to the aggravation of the downstream inflammatory response. Nrf2 is a key transcription factor that regulates the expression of antioxidant enzymes that protect against oxidative stress and tissue damage. We aimed to explore the underlying mechanism of OA development by investigating NLRP3, ASC, Nrf2, and HO-1 expression in synovia and their regulatory networks in OA. METHODS:Human total knee replacement samples were subjected to histology and micro-CT analysis to determine the pathological changes in the cartilage and subchondral bone and to assess the expression of inflammation-related markers in the synovial tissue by immunohistochemistry (IHC), qRT-PCR, and Western blot. To investigate these pathological changes in an OA animal model, adult Sprague-Dawley rats were subjected to anterior cruciate ligament transection and medial meniscectomy. Articular cartilage and subchondral bone changes and synovial tissue were also determined by the same methods used for the human samples. Finally, SW982 cells were stimulated with lipopolysaccharide (LPS) as an in vitro inflammatory cell model. The correlation between NLRP3 and Nrf2 expression was confirmed by knocking down NLRP3 or Nrf2. RESULTS:Cartilage destruction and subchondral bone sclerosis were found in the OA patients and OA model rats. Significantly increased expression levels of NLRP3, ASC, Nrf2, and HO-1 were found in the synovial tissue from OA patients. NLRP3, ASC, Nrf2, and HO-1 expression in the synovium was also upregulated in the OA group compared with the sham group. Furthermore, the NLRP3, Nrf2, HO-1, IL-1?, and IL-18 expression in LPS-treated SW982 cells was increased in a dose-dependent manner. As expected, the expression of NLRP3 was upregulated, and the expression of IL-1? and IL-18 was downregulated after Nrf2 silencing. However, knocking down NLRP3 did not affect the expression of Nrf2. CONCLUSIONS:ROS-induced oxidative stress may be the main cause of NLRP3 inflammasome activation and subsequent release of downstream factors during OA development. Nrf2/HO-1 signaling could be a key pathway for the activation of the NLRP3 inflammasome, which may contribute to the progression of OA. Herein, we discovered a novel role of Nrf2/HO-1 signaling in the production of NLRP3, which may facilitate the prevention and treatment of OA.

Dataset Information

Promoter Methylation Leads to Decreased ZFP36 Expression and Deregulated NLRP3 Inflammasome Activation in Psoriatic Fibroblasts.

Publications

Promoter Methylation Leads to Decreased <i>ZFP36</i> Expression and Deregulated NLRP3 Inflammasome Activation in Psoriatic Fibroblasts.

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