Targeting Tristetraprolin Expression or Functional Activity Regulates Inflammatory Response Induced by MSU Crystals.

Linxi Lv,Long Ren,Ting Qin,Jianpin Liu,Feng Chen,Yongen Xie,Qiushi Huang,Hui Jiang,Mei Zeng,Fan Long

doi:10.3389/fimmu.2021.675534

Abstract

The RNA-binding protein tristetraprolin (TTP) is an anti-inflammatory factor that prompts the mRNA decay of target mRNAs and is involved in inflammatory diseases such as rheumatoid arthritis (RA). TTP is regulated by phosphorylation, and protein phosphatase 2A (PP2A) can dephosphorylate TTP to activate its mRNA-degrading function. Some small molecules can enhance PP2A activation. Short interfering RNA (siRNA) targeting TTP expression or PP2A agonist (Arctigenin) was administered to monosodium urate (MSU) crystal-induced J774A.1 cells, and the expression of inflammatory related genes was detected by RT-PCR and Western blot assays. The effects of Arctigenin in mouse models of acute inflammation induced by MSU crystals, including peritonitis and arthritis, were evaluated. The data indicated that TTP expression levels and endogenous PP2A activity were increased in MSU-crystal treated J774A.1 cells. TTP knockdown exacerbated inflammation-related genes expression and NLRP3 inflammasome activation. However, PP2A agonist treatment (Arctigenin) suppressed MSU crystal-induced inflammation in J774A.1 cells. Arctigenin also relieved mitochondrial reactive oxygen species (mtROS) production and improved lysosomal membrane permeability in MSU crystal-treated J774A.1 cells. Moreover, TTP knockdown reversed the anti-inflammatory and antioxidant effects of Arctigenin. Oral administration of Arctigenin significantly alleviated foot pad swelling, the number of inflammatory cells in peritoneal lavage fluids and the production of IL-1β in the mouse model of inflammation induced by MSU crystals. Collectively, these data imply that targeting TTP expression or functional activity may provide a potential therapeutic strategy for inflammation caused by MSU crystals.

Highlights

Gout is caused by the deposition of monosodium urate (MSU) crystals in and around the joints [1]
The murine macrophages cell line J774A.1 has been widely used as a cell model to study the activation of NOD-like receptor family (NLRP3) inflammasomes due to its expression of NLRP3, Caspase-1 and ASC [17, 18]
Based on the established mouse model of gouty arthritis, the immunofluorescence data of mouse foot pad tissue sections showed that the number of TTP positive cells was significantly increased in the MSU crystal-treated group (Figure 1E), suggesting that TTP might be involved in MSU crystal-induced gouty arthritis

Summary

Introduction

Gout is caused by the deposition of MSU crystals in and around the joints [1]. Gout is the most common cause of inflammatory arthritis and its global epidemiology shows an increase in incidence and prevalence in both developed and developing countries [2]. Acute gout episodes are clinically described as arthritic pain and inflammation that, if left untreated, can develop into recurrent acute urate deposition (gout) and progressive joint destruction affecting the patient’s health [3, 4]. To date, the clinical use of drugs has often resulted in undesirable side effects. Countless efforts have failed to create an effective and safe agent to treat gout. A large number of studies have shown that TTP plays an important role in balancing the inflammatory response [6] and plays a potential antitumor role by mediating the levels of proinflammatory cytokines such as IL-1b, TNF-a, IL-6 and COX-2 [7,8,9]

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Results

Conclusion