The NLRP3 inflammasome affects DNA damage responses after oxidative and genotoxic stress in dendritic cells

Abstract

The NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is a cytoplasmic protein complex that mediates inflammatory responses to a broad array of danger signals. The inflammasome drives caspase-1 activation and promotes secretion of the pro-inflammatory cytokines IL-1β and IL-18, and might also participate in other cellular processes. Here, we tried to identify new pathways regulated by the NLRP3 inflammasome in murine dendritic cells (DCs) in response to monosodium urate (MSU) crystals. Using a transcriptomic approach, we found that DCs fromAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMulticellular organisms are constantly exposed to environmental assaults and have evolved several mechanisms that either promote cellular repair or induce cell death in order to maintain Correspondence: Dr. Alessandra Mortellaro e-mail: alessandra_mortellaro@immunol.a-star.edu.sg tissue integrity. In particular, the immune system has evolved specialized innate cells that mediate recognition of invading microbes and host perturbations to initiate a potent set of defense mechanisms. To this end, innate cells are equipped with a * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2126-2137 Innate immunity 2127 range of surface and intracellular receptors that recognize both microbial-associated molecular patterns and danger-associated molecular patterns (DAMPs). When damage is not repairable, the damaged cells die and release a multitude of poorly defined DAMPs, which in turn elicit an inflammatory response. Inflammation can be both good and bad, depending on the situation. The NOD-like receptor (NLR) family pyrin domaincontaining 3 (NLRP3) inflammasome is a multiprotein complex, which can drive inflammatory responses by promoting the release of IL-1β and IL-18 from innate cells [1]. Through the adaptor protein ASC (apoptosis-associated specklike protein containing a CARD domain), NLRP3 recruits and activates caspase-1, leading to cleavage and activation of IL-1β and IL-18 precursors. Recent studies have identified a variety of NLRP3 inflammasome activators including whole live bacteria, fungal and viral pathogens, as well as various microbial-associated molecular patterns and DAMPs [2]. In addition, cellular stress triggered by factors ranging from oxidative stress to lysosomal damage appears sufficient to activate NLRP3 [3].The mechanisms by which these molecules of diverse origins and structures can each trigger the NLRP3 inflammasome remain unclear. However, the generation of ROS seems to be a unifying factor, consistently mediating NLRP3 activation across several stimuli [4]. Recently, Zhou and colleagues demonstrated that mitochondrial (mt) ROS are critical for NLRP3 inflammasome activation [5]. Accumulation of ROS-producing mitochondria either by repressing mitochondrial autophagy or by pharmacological inhibition of the mitochondri...

DNA damage response impacts macrophage functions

“…The study included only 7 cases with MYC/ BCL6-DH but, interestingly, 6 of them were non-GCB and had a tendency to better prognosis than cases with MYC/BCL2-DH, which occurs almost exclusively in GCB tumors. Previous reports on the prognostic value of MYC/BCL6-DH have been controversial, 5,8 but the findings in the current study suggest that MYC/BCL6 may have a different biological meaning than MYC/BCL2 in DH tumors. One intriguing aspect in the CopieBergman et al study is the better-than-expected outcome of patients with MYC alterations, independent of the translocated partner or subtype of DH lesions, compared with the poor outcome reported in the majority of previous publications.…”

“…Several studies have shown that infective agents and microbial products can induce DSBs either directly or indirectly through reactive oxygen species (ROS). [3][4][5] Moreover, unrepaired DSBs activate the cytosolic DNA sensor stimulator of interferon genes, thus inducing the production of interferon alpha and interferon beta, which promote innate immune responses. [6][7][8] Pereira-Lopes et al broaden our knowledge of the physiologic functions of DDR in innate immunity, demonstrating for the first time that multiple macrophage functions are controlled by DDR, in particular, by the Nijmegen breakage syndrome 1 (NBS1) protein, the component of the MRN complex that is responsible for translocation of the MRN complex into the nucleus.…”

Regulation of Mouse Microglia Activation and Effector Functions by Bone Marrow-Derived Mesenchymal Stem Cells

“…Too high an NALP3 level could be dangerous for microglia by inducing pyroptosis, a caspase-1-dependent form of programmed cell death [50]. In line with this, Licandro et al [51] recently suggested that NALP3 modulates a number of signal pathways involved in DNA damage response and apoptosis. Finally, the most intriguing aspect of this study is the enhanced proliferation of in vivo primed, antigen-specific T lymphocytes in MG-MSC cocultures, that is, the increased antigen-presenting ability of microglia on MSC coculture.…”

Reactive oxygen species at the crossroads of inflammasome and inflammation

“…Additionally, studies conducted using monosodium urate (MSU) crystals in murine dendritic cells (DC) from Nlrp3 −/− mice suggest the role of inflammasomes in the disease process. DCs from Nlrp3 −/− mice respond differently to MSU or other ROS-mobilizing stimuli (rotenone and γ-radiation) compared to DCs from WT mice (Licandro et al, 2013). Furthermore, DNA fragmentation is markedly reduced in DCs from Nlrp3 −/− and Casp-1 −/− mice compared to those from WT mice.…”