Neutrophil Extracellular Trap–Associated Protein Activation of the NLRP3 Inflammasome Is Enhanced in Lupus Macrophages
01 Feb 2013-Journal of Immunology (American Association of Immunologists)-Vol. 190, Iss: 3, pp 1217-1226
TL;DR: It is suggested that enhanced formation of NETs in lupus patients can lead to increased inflammasome activation in adjacent macrophages, resulting in a feed-forward inflammatory loop that could potentially lead to disease flares and/or organ damage.
Abstract: Neutrophil extracellular traps (NETs) represent an important defense mechanism against microorganisms. Clearance of NETs is impaired in a subset of patients with systemic lupus erythematosus, and NETosis is increased in neutrophils and, particularly, in low-density granulocytes derived from lupus patients. NETs are toxic to the endothelium, expose immunostimulatory molecules, activate plasmacytoid dendritic cells, and may participate in organ damage through incompletely characterized pathways. To better understand the role of NETs in fostering dysregulated inflammation, we examined inflammasome activation in response to NETs or to LL-37, an antibacterial protein externalized on NETs. Both NETs and LL-37 activate caspase-1, the central enzyme of the inflammasome, in both human and murine macrophages, resulting in release of active IL-1β and IL-18. LL-37 activation of the NLRP3 inflammasome utilizes P2X7 receptor-mediated potassium efflux. NET and LL-37-mediated activation of the inflammasome is enhanced in macrophages derived from lupus patients. In turn, IL-18 is able to stimulate NETosis in human neutrophils. These results suggest that enhanced formation of NETs in lupus patients can lead to increased inflammasome activation in adjacent macrophages. This leads to release of inflammatory cytokines that further stimulate NETosis, resulting in a feed-forward inflammatory loop that could potentially lead to disease flares and/or organ damage.
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TL;DR: The NLRP3 inflammasome mediates pro-inflammatory responses and pyroptotic cell death and how it is being targeted to treat inflammatory diseases is described.
Abstract: NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical bases of NLRP3 activation and regulation and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.
2,097 citations
The Feinstein Institute for Medical Research1, Cold Spring Harbor Laboratory2, Cornell University3, Hofstra University4, McGill University5, University of Michigan6, University of California, San Francisco7, University of Texas MD Anderson Cancer Center8, McGill University Health Centre9, University of Utah10
TL;DR: Autopsy results and literature are presented supporting the hypothesis that neutrophil extracellular traps (NETs) may contribute to organ damage and mortality in COVID-19, and existing drugs that target NETs, although unspecific, may benefit CO VID-19 patients.
Abstract: Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.
1,138 citations
TL;DR: Findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases.
Abstract: Neutrophil extracellular traps (NETs) are implicated in autoimmunity, but how they are generated and their roles in sterile inflammation remain unclear. Ribonucleoprotein immune complexes (RNP ICs), inducers of NETosis, require mitochondrial reactive oxygen species (ROS) for maximal NET stimulation. After RNP IC stimulation of neutrophils, mitochondria become hypopolarized and translocate to the cell surface. Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro, and when this DNA is injected into mice, it stimulates type I interferon (IFN) signaling through a pathway dependent on the DNA sensor STING. Mitochondrial ROS are also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus. This was also observed in individuals with chronic granulomatous disease, who lack NADPH oxidase activity but still develop autoimmunity and type I IFN signatures. Mitochondrial ROS inhibition in vivo reduces disease severity and type I IFN responses in a mouse model of lupus. Together, these findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases.
967 citations
TL;DR: The evidence that neutrophil extracellular traps (NETs) play a critical role in innate immunity is examined and how infections are related to the development of autoimmune and vasculitic diseases through unintended but detrimental bystander damage resulting from NET release is examined.
723 citations
Cites background from "Neutrophil Extracellular Trap–Assoc..."
...Additionally, macrophages from lupus patients are highly sensitive to NET-induced activation through the NLRP3 inflammasome, thereby contributing to a feedforward proinflammatory response, further compounding disease progression and severity.(128) Rheumatoid arthritis (RA) is an autoimmune disease that targets joints, but it can also cause severe systemic and solid organ complications....
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TL;DR: These findings support a model whereby the NLRP3 inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.
Abstract: Assembly of the NLRP3 inflammasome activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β and thereby serves a central role in the inflammatory response and in diverse human diseases. Here we found that upon activation of caspase-1, oligomeric NLRP3 inflammasome particles were released from macrophages. Recombinant oligomeric protein particles composed of the adaptor ASC or the p.D303N mutant form of NLRP3 associated with cryopyrin-associated periodic syndromes (CAPS) stimulated further activation of caspase-1 extracellularly, as well as intracellularly after phagocytosis by surrounding macrophages. We found oligomeric ASC particles in the serum of patients with active CAPS but not in that of patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3 inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.
655 citations
References
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TL;DR: The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification and showed gains in sensitivity and specificity.
Abstract: The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification. The 1982 revised criteria include fluorescence antinuclear antibody and antibody to native DNA and Sm antigen. Some criteria involving the same organ systems were aggregated into single criteria. Raynaud's phenomenon and alopecia were not included in the 1982 revised criteria because of low sensitivity and specificity. The new criteria were 96% sensitive and 96% specific when tested with SLE and control patient data gathered from 18 participating clinics. When compared with the 1971 criteria, the 1982 revised criteria showed gains in sensitivity and specificity.
14,272 citations
"Neutrophil Extracellular Trap–Assoc..." refers methods in this paper
...To be enrolled in this study, lupus patients fulfilled the revised American College of Rheumatology criteria for SLE (21) and were enrolled from the University of Michigan Outpatient Rheumatology Clinic....
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TL;DR: A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention and provide a paradigm for macrophage plasticity and function.
Abstract: Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention.
3,133 citations
"Neutrophil Extracellular Trap–Assoc..." refers background or result in this paper
...Mf derived in the presence of GM-CSF were CD11c, Tie-2, and F4/80, consistent with an M1 phenotype (25)....
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...Mf derived in L cell–conditioned media were Tie-2, F4/80, and CD11c, consistent with M2 (25)....
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TL;DR: The main functions of polarized macrophages are reviewed and the perspectives of this field are discussed, which include high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion.
Abstract: Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized macrophages can be broadly classified in two main groups: classically activated macrophages (or M1), whose prototypical activating stimuli are IFNgamma and LPS, and alternatively activated macrophages (or M2), further subdivided in M2a (after exposure to IL-4 or IL-13), M2b (immune complexes in combination with IL-1beta or LPS) and M2c (IL-10, TGFbeta or glucocorticoids). M1 exhibit potent microbicidal properties and promote strong IL-12-mediated Th1 responses, whilst M2 support Th2-associated effector functions. Beyond infection M2 polarized macrophages play a role in resolution of inflammation through high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion. Similar functions are also exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumoral role. Here we review the main functions of polarized macrophages and discuss the perspectives of this field.
2,836 citations
"Neutrophil Extracellular Trap–Assoc..." refers background in this paper
...70% CD86, MHC class II, and CD36, consistent with an M1 phenotype as previously reported (24)....
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TL;DR: This novel ROS-dependent death allows neutrophils to fulfill their antimicrobial function, even beyond their lifespan.
Abstract: Neutrophil extracellular traps (NETs) are extracellular structures composed of chromatin and granule proteins that bind and kill microorganisms. We show that upon stimulation, the nuclei of neutrophils lose their shape, and the eu- and heterochromatin homogenize. Later, the nuclear envelope and the granule membranes disintegrate, allowing the mixing of NET components. Finally, the NETs are released as the cell membrane breaks. This cell death process is distinct from apoptosis and necrosis and depends on the generation of reactive oxygen species (ROS) by NADPH oxidase. Patients with chronic granulomatous disease carry mutations in NADPH oxidase and cannot activate this cell-death pathway or make NETs. This novel ROS-dependent death allows neutrophils to fulfill their antimicrobial function, even beyond their lifespan.
2,481 citations
TL;DR: It is shown that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 and myeloperoxidase (MPO).
Abstract: Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.
1,394 citations
"Neutrophil Extracellular Trap–Assoc..." refers background in this paper
...TNF and IL-1b have been reported to stimulate NET formation (2, 31)....
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