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

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.

Lipoxin A4 attenuates MSU-crystal-induced NLRP3 inflammasome activation through suppressing Nrf2 thereby increasing TXNRD2

“…We next determined whether LXA4 can hamper the upstream event dependent on NLRP3 inflammasome activation. Previous studies have confirmed that chloride efflux, potassium efflux, and ROS production are important upstream events for activation of NLRP3 inflammasome ( 15 , 16 , 36 , 37 ). The MQAE is a fluorescence probe for intracellular chloride ions; the higher intensity of MQAE fluorescence shows a lower level of intracellular chloride ions and vice versa .…”

NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases

“…The deficiency of A20 in macrophages can enhance the effect of NLRP3 inflammasome by promoting the biological activity of caspase-1, IL-1β secretion, and pyroptosis in mouse models ( 44 ). Activation of NLRP3 Inflammasome and secretion of IL-1β can be inhibited by TTP expression and activation of TTP in both in vivo and in vitro models ( 95 ). TTP can be activated by dephosphorylation mediated by protein phosphatase 2A (PP2A), and Arctigenin (PP2A agonist) reduces monosodium urate (MSU) crystal-induced inflammation ( 95 ).…”

“…Activation of NLRP3 Inflammasome and secretion of IL-1β can be inhibited by TTP expression and activation of TTP in both in vivo and in vitro models ( 95 ). TTP can be activated by dephosphorylation mediated by protein phosphatase 2A (PP2A), and Arctigenin (PP2A agonist) reduces monosodium urate (MSU) crystal-induced inflammation ( 95 ). It is indicated that TTP might be a potential target for inflammation induced by MSU crystals ( 95 ).…”

“…TTP can be activated by dephosphorylation mediated by protein phosphatase 2A (PP2A), and Arctigenin (PP2A agonist) reduces monosodium urate (MSU) crystal-induced inflammation ( 95 ). It is indicated that TTP might be a potential target for inflammation induced by MSU crystals ( 95 ). These studies indicate that treatments aiming to inhibit NLRP3 inflammasome and IL-1β might be potential therapy for RA.…”

ZFP36 ring finger protein like 1 significantly suppresses human coronavirus OC43 replication

“…Among various ZFPs, the CCCH-type ZFP family contains zinc ions that coordinate protein structure by binding to cystine-cystine or cysteines-histidine amino acids ( Abbehausen, 2019 ; Hajikhezri et al, 2020 ). The CCCH-type ZFP family has also been characterized for its antiviral ( Hajikhezri et al, 2020 ; Tang, Wang & Gao, 2017 ; Zhang et al, 2020 ; Guo et al, 2004 ; Zhao et al, 2019 ; Gao, Guo & Goff, 2002 ; Zhu et al, 2020 ; Musah, 2004 ; Chen, Jeng & Lai, 2017 ; Scozzafava et al, 2003 ; Schito et al, 2006 ; Angiolilli et al, 2021 ) and immune modulator activity ( Wang et al, 2015 ; Tu et al, 2019 ; Haneklaus et al, 2017 ; Lv et al, 2021 ; Matsushita et al, 2009 ; Wawro, Kochan & Kasza, 2016 ; Uehata & Akira, 2013 ; Chen et al, 2018 ; Mino et al, 2015 ; Fu & Blackshear, 2017 ; Stumpo, Lai & Blackshear, 2010 ; Shrestha, Pun & Park, 2018 ; Kontoyiannis, 2018 ).…”