MicroRNA‐130b Ameliorates Murine Lupus Nephritis Through Targeting the Type I Interferon Pathway on Renal Mesangial Cells

Arthritis & Rheumatology

Berthier

Kahlenberg

2017

Objective The inflammasome complex is a driver of organ damage in systemic lupus erythematosus (SLE). While type I interferons (IFNs) are well established as mediators of SLE pathogenesis, their role in inflammasome activation in SLE has not been assessed. Thus, we examined type I IFNs as regulators of the inflammasome and identified interferon regulatory factor 1 (IRF1) as critical for inflammasome hyperactivity in SLE. Methods SLE patients fulfilled ≥4 ACR criteria and were recruited from the University of Michigan Lupus Cohort. Primary monocytes were isolated from SLE patients or healthy controls by negative selection, treated with inflammasome activators in the presence or absence of IFNα, and IL-1β secretion was measured by ELISA. Expression levels of interferon and inflammasome-related molecules were assessed by real-time PCR and Western blotting. IRF1 expression was specifically downregulated by siRNA transfection and a chemical inhibitor. Results SLE monocytes exhibited increased expression and enhanced activation of the inflammasome by ATP when compared to control monocytes. Expression of inflammasome and interferon-regulated genes was significantly correlated in lupus, but not control, monocytes. Inflammasome activity was increased after prolonged exposure to IFNα. Reduction of IRF1 expression via siRNA blocked caspase-1 upregulation after treatment with IFNα. Importantly, hyperactivity of the inflammasome in lupus monocytes was significantly reduced after knock-down or inhibition of IRF1. Conclusion Prolonged type I IFN exposure, as seen in SLE patients, primes monocytes for robust inflammasome activation in an IRF1-dependent manner. IRF1 inhibition may serve as a novel target for treatment of SLE-associated inflammation and organ damage.

Section: Resultsmentioning

confidence: 99%

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

Arthritis & Rheumatology

Berthier

Kahlenberg

2017

“…Monocytes from active lupus patients expressed significant lower miRNA-302d, which is associated with increased interferon regulatory factor (IRF)-9 both in patients and pristine induce lupus model [59]. Moreover, in kidney tissues of lupus patients and mice model, renal mesangial cells express much lower miRNA-302d, which is negatively correlated with its target gene IRF-1 [60]. Cheng, et al found that miRNA-451a increased in both spleen and thymus tissues in lupus mice model.…”

Section: Extracellular Rna and Slementioning

confidence: 99%

Extracellular RNA in systemic lupus erythematosus

Wang

2019

ExRNA

Since the discovery of extracellular RNA (exRNA), it has been shown that exRNAs play a significant role as a transducer in intercellular communication and biomarkers in various diseases. Systemic lupus erythematosus (SLE) is a kind of autoimmune disease that has protean manifestations. The survival and long-term prognosis of patients with SLE has improved in these 5-10 years, while disease pathogenesis is still not clear. Many researchers found the changes in exRNA profile, and exRNAs are likely participating in the process of SLE. In this review, we summarize the current profile and function of exRNA in SLE. Circulating miRNAs, in particular, have been identified as biomarkers for SLE diagnosis. We also explore the function of lncRNA in SLE and the potential correlation with disease progression and activity. These studies show that exRNAs may take parts in the process of SLE and some of them can be used as diagnostic tool for SLE.

“…Although the investigators did not identify which cells synthesized type I IFN, it is possible that mesangial cells contribute 49 . Regulation of type I IFN in mesangial cells is mediated at least in part by microRNA (miR)-130b, and miR-130b expression is decreased in renal specimens from patients and mice with LN 50 .…”

Section: Recent Knowledge On Renal Inflammation In Lupus Nephritismentioning

confidence: 99%

Recent advances in the understanding of renal inflammation and fibrosis in lupus nephritis

2017

Lupus nephritis is a potentially reversible cause of severe acute kidney injury and is an important cause of end-stage renal failure in Asians and patients of African or Hispanic descent. It is characterized by aberrant exaggerated innate and adaptive immune responses, autoantibody production and their deposition in the kidney parenchyma, triggering complement activation, activation and proliferation of resident renal cells, and expression of pro-inflammatory and chemotactic molecules leading to the influx of inflammatory cells, all of which culminate in destruction of normal nephrons and their replacement by fibrous tissue. Anti-double-stranded DNA (anti-dsDNA) antibody level correlates with disease activity in most patients. There is evidence that apart from mediating pathogenic processes through the formation of immune complexes, pathogenic anti-dsDNA antibodies can bind to resident renal cells and induce downstream pro-apoptotic, pro-inflammatory, or pro-fibrotic processes or a combination of these. Recent data also highlight the critical role of macrophages in acute and chronic kidney injury. Though clinically effective, current treatments for lupus nephritis encompass non-specific immunosuppression and the anti-inflammatory action of high-dose corticosteroids. The clinical and histological impact of novel biologics targeting pro-inflammatory molecules remains to be investigated. Insight into the underlying mechanisms that induce inflammatory and fibrotic processes in the kidney of lupus nephritis could present opportunities for more specific novel treatment options to improve clinical outcomes while minimizing off-target untoward effects. This review discusses recent advances in the understanding of pathogenic mechanisms leading to inflammation and fibrosis of the kidney in lupus nephritis in the context of established standard-of-care and emerging therapies.