PARP-1 regulates inflammasome activity by poly-ADP-ribosylation of NLRP3 and interaction with TXNIP in primary macrophages

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) plays an essential role in DNA repair by catalyzing the polymerization of ADP-ribose unit to target proteins. Several studies have shown that PARP-1 can regulate inflammatory responses in various disease models. The intracellular Nod-like receptor NLRP3 has emerged as the most crucial innate immune receptor because of its broad specificity in mediating immune response to pathogen invasion and danger signals associated with cellular damage. In our study, we found NLRP3 stimuli-induced caspase-1 maturation and IL-1β production were impaired by PARP-1 knockout or PARP-1 inhibition in bone marrow-derived macrophages (BMDM). The step 1 signal of NLRP3 inflammasome activation was not affected by PARP-1 deficiency. Moreover, ATP-induced cytosolic ROS production was lower in Parp-1−/− BMDM, resulting in the decreased inflammasome complex assembly. PARP-1 can translocate to cytosol upon ATP stimulation and trigger the PARylation modification on NLRP3, leading to NLRP3 inflammasome assembly. PARP-1 was also a bridge between NLRP3 and thioredoxin-interacting protein (TXNIP) and participated in NLRP3/TXNIP complex formation for inflammasome activation. Overall, PARP-1 positively regulates NLRP3 inflammasome activation via increasing ROS production and interaction with TXNIP and NLRP3, leading to PARylation of NLRP3. Our data demonstrate a novel regulatory mechanism for NLRP3 inflammasome activation by PARP-1. Therefore, PARP-1 can serve as a potential target in the treatment of IL-1β associated inflammatory diseases.

Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury

“…The efficacy of PARP inhibitors in the post-treatment setting also indicates that the site of PARP inhibitors’ beneficial effect in the current model includes cellular and molecular targets that are continuously ongoing and/or become later activated during the sequelae of various pathophysiological events, as opposed to interfering with early triggers of injury. The pathophysiological pathways that were affected by PARP inhibition both in co-treatment and post-treatment regimens included many pathways and targets which have previously been implicated in the anti-inflammatory or therapeutic effect of PARP inhibitors in various non-oncological disease models, including NF-κB [ 24 , 44 , 45 , 56 , 57 ]; the production of various chemokines, such as MIP-1α [ 46 ]; modulation of the production of various cytokines [ 14 , 15 , 16 , 17 , 29 , 30 , 47 ]; inhibition of inflammatory cell mobilization and recruitment [ 7 , 8 , 14 , 29 , 58 ]; and more recently implicated pathways, including the activation of the NLRP3 inflammasome [ 29 , 59 ]. Regarding the effect of PARP inhibition on the expression of β-catenin, the current study shows that PARP inhibition suppresses the expression of this mediator during ALI.…”

A Double-Edged Sword: The Two Faces of PARylation

“…Several studies have elucidated the relationships between PARylation and inflammasomes [ 17 , 55 , 56 ]. Dysregulation of inflammasome formation occurs in several diseases, including cancer, type 2 diabetes, chronic asthma-associated airway inflammation, Huntington’s disease, and experimental autoimmune encephalomyelitis, affecting cell viability [ 17 , 55 , 56 , 57 ]. Inflammasome formation has been studied for two decades as an important structural feature in various inflammatory diseases.…”

“…Receptors such as toll-like receptors (TLRs) or tumor necrosis factor receptors (TNFRs) are activated by pathogenic factors to form inflammasomes. PARylation by PARPs positively regulates inflammasome activation [ 17 ]. The PARylation of p65-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) regulates its nuclear retention and interactions with exportin 1, suggesting that PARylation might modulate the expression of inflammatory genes and inflammatory processes ( Figure 2 ) [ 58 ].…”

“…This phenomenon induces chromatin remodeling and recruits other DNA repair proteins. However, recent studies have suggested novel roles for PARylation in inflammation, metabolism, and cell death [ 16 , 17 , 18 , 19 ]. In this review, we discuss recent findings on the roles of PARylation.…”

P2X7 Activation Enhances Lipid Accumulation During Adipocytes Differentiation Through Suppressing the Expression of Sirtuin-3, Sirtuin-5, and Browning Genes

“…Such a large pore allows molecules with molecular weight up to 900 Da to enter the cells. Consequently, it initiates several cellular events, including nucleotide-binding domain leucine-rich repeat family pyrin domain-containing protein 3 (NLRP3) inflammasome formation, the opening of pannexin 1 and connexin hemichannels, membrane blebbing, reactive oxygen species (ROS) production, loss of mitochondrial membrane potential, and eventually cellular death ( Schroder and Tschopp, 2010 ; Idzko et al, 2014 ; Lin et al, 2015 ; Di Virgilio et al, 2017 ; Sekar et al, 2018 ; Chiu et al, 2022 ). P2X7 is widely expressed in several tissues, but it is not highly expressed in white or brown adipose tissues unless activated upon pharmacological agents or pathological environments ( Jain and Jacobson, 2021 ).…”