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

Ling-Ya Chiu,Duen-Yi Huang,Wan-Wan Lin,Wan-Wan Lin,Wan-Wan Lin

doi:10.1007/s00018-022-04138-z

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.

Highlights

Poly(ADP-ribose) polymerase-1 (PARP-1), which stands for poly(ADP-ribose) polymerase-1, is a multifunctional nuclear enzyme and has key roles in DNA repair, chromatin replication, transcriptional regulation and cell death [1,2,3,4]
After LPS priming for 6 h, WT or Parp-1−/− macrophages were treated with different NLRP3 activators, including adenosine triphosphate (ATP) (Fig. 1a), aluminum gel (Alu) and Monosodium urate (MSU) (Fig. 1b) for different times
In LPS-primed bone marrow-derived macrophages (BMDM), we found that UVB can induce IL-1β secretion in dose-dependent and time-dependent manners and this effect was decreased in Parp-1−/− BMDM (Fig. 1d and e) and in Nlrp3−/− BMDM (Fig. 1f)

Summary

Introduction

PARP-1, which stands for poly(ADP-ribose) polymerase-1, is a multifunctional nuclear enzyme and has key roles in DNA repair, chromatin replication, transcriptional regulation and cell death [1,2,3,4]. Previous studies have shown that reactive oxygen species (ROS), potassium efflux, lysosomal rupture, and oxidized mitochondrial DNA releasing from damaged mitochondria are potential activators of the NLRP3 inflammasome assembly [17,18,19,20,21,22]. In this aspect, thioredoxin-interacting protein (TXNIP) has been demonstrated to mediate NLRP3 inflammasome activation. After the stimulation of NLRP3 activators, TNXIP can dissociate from TRX and bind with NLRP3 for activation of inflammasome [18, 23]

Methods

Results

Conclusion