Deregulated NLRP3 and NLRP1 Inflammasomes and Their Correlations with Disease Activity in Systemic Lupus Erythematosus

Yang, Qingrui; Yu, Chengcheng; Yang, Zepeng; Wei, Qing; Mu, Kun; Zhang, Ying; Zhao, Wei; Wang, Xiaofeng; Huai, Wanwan; Han, Lihui

doi:10.3899/jrheum.130310

Cited by 73 publications

(38 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, although our data suggest a role of inflammasome-mediated In contrast, NLRP3, CASP1 and IL1B mRNA levels were found to be decreased in PBMC from patients with autoimmune diseases, such as SLE patients (16) or patients with rheumatoid arthritis, as compared with age-and sex-matched healthy individuals (17). PBMC are a mix of different peripheral immune cells, composed of monocytes, B-and T-lymphocytes.…”

Section: Discussionmentioning

confidence: 52%

Sex- and Disease-Specific Inflammasome Signatures in Circulating Blood Leukocytes of Patients with Abdominal Aortic Aneurysm

Cakmak

Wortmann

et al. 2016

Mol Med

View full text Add to dashboard Cite

Male sex is a risk factor for abdominal aortic aneurysm (AAA). Within the AAA adventitia, infiltrating leukocytes express high levels of inflammasome components. To further elucidate the role of inflammatory cells in the pathogenesis of AAA, we here addressed expression and functionality of inflammasome components in peripheral blood mononuclear cells (PBMC) of AAA patients in association with sex. PBMC and plasma were isolated from 100 vascular patients, including 34 pairs of AAA patients and age/sexmatched non-AAA patients. Male PBMC were found to express significantly higher mRNA levels of AIM2, NLRP3, ASC (PYCARD), CASP1, CASP5, and IL1B (all P < 0.0001) than female PBMC. Within the male patients, PBMC of AAA patients displayed increased mRNA levels of NLRP3 (P = 0.044), CASP1 (P = 0.032) and IL1B (P = 0.0004) compared with matched non-AAA PBMC, whereas there was no difference between female AAA and non-AAA patients. The relative protein level of NLRP3 was significantly lower in PBMC lysates from all AAA patients than in matched controls (P = 0.038), whereas AIM2 and active Caspase-1 (p10) protein levels were significantly increased (P = 0.014 and P = 0.049). ELISA revealed significantly increased IL-1α (mean = 6.34 versus 0.01 pg/mL) and IL-1β plasma levels (mean = 12.07 versus 0.04 pg/mL) in AAA patients. The data indicate that male PBMC display a systemic proinflammatory state with primed inflammasomes that may contribute to AAA-pathogenesis. The AAA-specific inflammasome activation pattern suggests differential regulation of the sensors AIM2 and NLRP3 in inflammatory cells of AAA patients.

show abstract

Section: Discussionmentioning

confidence: 52%

Sex- and Disease-Specific Inflammasome Signatures in Circulating Blood Leukocytes of Patients with Abdominal Aortic Aneurysm

Cakmak

Wortmann

et al. 2016

Mol Med

View full text Add to dashboard Cite

show abstract

“…An increase in expression of the pro-inflammatory cytokine IL-1β has been noted in the cutaneous lesion and Peripheral Blood Mononuclear Cells (PBMCs) from lupus patients (Yang et al, 2014). IL-1β promotes a Th17 cell response, which is increased in lupus.…”

Section: Inflammasomes In Human Pathological Conditionsmentioning

confidence: 99%

Reactive oxygen species at the crossroads of inflammasome and inflammation

2014

View full text Add to dashboard Cite

Inflammasomes form a crucial part of the innate immune system. These are multi-protein oligomer platforms that are composed of intracellular sensors which are coupled with caspase and interleukin activating systems. Nod-like receptor protein (NLRP) 3, and 6 and NLRC4 and AIM2 are the prominent members of the inflammasome family. Inflammasome activation leads to pyroptosis, a process of programmed cell death distinct from apoptosis through activation of Caspase and further downstream targets such as IL-1β and IL-18 leading to activation of inflammatory cascade. Reactive oxygen species (ROS) serves as important inflammasome activating signals. ROS activates inflammasome through mitogen-activated protein kinases (MAPK) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Dysregulation of inflammasome plays a significant role in various pathological processes. Viral infections such as Dengue and Respiratory syncytial virus activate inflammasomes. Crystal compounds in silicosis and gout also activate ROS. In diabetes, inhibition of autophagy with resultant accumulation of dysfunctional mitochondria leads to enhanced ROS production activating inflammasomes. Activation of inflammasomes can be dampened by antioxidants such as SIRT-1. Inflammasome and related cascade could serve as future therapeutic targets for various pathological conditions.

show abstract

“…Further, two cytosolic sensors that recognize dsDNA (p202 and absent in melanoma 2; AIM2) have been implicated in type 1 interferon (IFN) production in murine lupus (24,25). The involvement of other cytosolic sensors, including NLRP3/ NLRP1 (26,27) and STING (28,29), have been more controversial. Despite the mounting evidence implicating cell debris in the activation of innate sensors, a mechanism explaining how IgG-ICs gain access to the cytosol and chronically activate intracellular receptors/sensors has never been resolved.…”

mentioning

confidence: 99%

Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

Monteith

Kang

Scott

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Defects in clearing apoptotic debris disrupt tissue and immunological homeostasis, leading to autoimmune and inflammatory diseases. Herein, we report that macrophages from lupus-prone MRL/lpr mice have impaired lysosomal maturation, resulting in heightened ROS production and attenuated lysosomal acidification. Impaired lysosomal maturation diminishes the ability of lysosomes to degrade apoptotic debris contained within IgG-immune complexes (IgG-ICs) and promotes recycling and the accumulation of nuclear self-antigens at the membrane 72 h after internalization. Diminished degradation of IgG-ICs prolongs the intracellular residency of nucleic acids, leading to the activation of Toll-like receptors. It also promotes phagosomal membrane permeabilization, allowing dsDNA and IgG to leak into the cytosol and activate AIM2 and TRIM21. Collectively, these events promote the accumulation of nuclear antigens and activate innate sensors that drive IFNα production and heightened cell death. These data identify a previously unidentified defect in lysosomal maturation that provides a mechanism for the chronic activation of intracellular innate sensors in systemic lupus erythematosus.

show abstract

Deregulated NLRP3 and NLRP1 Inflammasomes and Their Correlations with Disease Activity in Systemic Lupus Erythematosus

Abstract: These results indicated deregulation of NLRP3/NLRP1 inflammasomes in patients with SLE, and suggested an important role for inflammasomes in the pathogenesis and progression of SLE.

Cited by 73 publications

References 29 publications

Sex- and Disease-Specific Inflammasome Signatures in Circulating Blood Leukocytes of Patients with Abdominal Aortic Aneurysm

Sex- and Disease-Specific Inflammasome Signatures in Circulating Blood Leukocytes of Patients with Abdominal Aortic Aneurysm

Reactive oxygen species at the crossroads of inflammasome and inflammation

Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

Contact Info

Product

Resources

About