Neutrophil Extracellular Trap–Associated Protein Activation of the NLRP3 Inflammasome Is Enhanced in Lupus Macrophages
Open Access
- 1 February 2013
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 190 (3), 1217-1226
- https://doi.org/10.4049/jimmunol.1202388
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.This publication has 48 references indexed in Scilit:
- P2X7 receptor regulation of non-classical secretion from immune effector cellsCellular Microbiology, 2012
- ER stress activates the NLRP3 inflammasome via an UPR-independent pathwayCell Death & Disease, 2012
- Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodiesArthritis Research & Therapy, 2012
- LL37 and Cationic Peptides Enhance TLR3 Signaling by Viral Double-stranded RNAsPLOS ONE, 2011
- Cytosolic DNA Triggers Inflammasome Activation in Keratinocytes in Psoriatic LesionsScience Translational Medicine, 2011
- Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus ErythematosusScience Translational Medicine, 2011
- Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA–Peptide Complexes in Systemic Lupus ErythematosusScience Translational Medicine, 2011
- Impairment of neutrophil extracellular trap degradation is associated with lupus nephritisProceedings of the National Academy of Sciences of the United States of America, 2010
- Netting neutrophils in autoimmune small-vessel vasculitisNature Medicine, 2009
- Novel cell death program leads to neutrophil extracellular trapsThe Journal of cell biology, 2007