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

Abstract

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.

The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity

“…We then compared our mouse skin RNA-seq results to transcriptomic data from skin of cutaneous lupus patients (7). Genes dysregulated in lesional skin of patients with DLE or subacute cutaneous lupus erythematosus (SCLE) were overrepresented among transgenic DEGs (DLE, P = 1.1 × 10 -13 ; SCLE, P = 5.0 × 10 -9 ) and showed widespread upregulation in transgenic mice ( Figure 2D), revealing a shared pattern of gene dysregulation in skin of K5-Vgll3-transgenic mice and lupus patients.…”

Advances in Disease Mechanisms and Translational Technologies: Clinicopathologic Significance of Inflammasome Activation in Autoimmune Diseases

“…These include monosodium urate monohydrate and calcium pyrophosphate dihydrate (CPPD) crystals, which are responsible for gout and pseudogout, respectively (10), as well as double-stranded DNA (dsDNA) and U1 small nuclear RNP (U1 snRNP)-containing lupus immune complexes ( Figure 2) (11,12). Also, monocytes and macrophages in patients with rheumatic diseases, especially SLE, have increased expression of inflammasome components and/or enhanced inflammasome activation (13,14), suggesting the existence of an intrinsic alteration in the intracellular inflammasome pathways. Of note, some polymorphisms of inflammasome-related genes have been shown to be associated with susceptibility, severity, and/or treatment response in rheumatic diseases, including SLE and RA (15)(16)(17)(18)(19)(20).…”

“…Monocytes and macrophages from patients with SLE appear to be more prone to inflammasome activation (13,14). Patients with SLE have enhanced inflammasome activation in monocyte-derived macrophages upon NET and LL-37 stimulation (13).…”

“…Patients with SLE have enhanced inflammasome activation in monocyte‐derived macrophages upon NET and LL‐37 stimulation . Also, freshly isolated monocytes from patients with SLE demonstrate increased expression of NLRP3 , AIM2, and CASP1 . The expression of these genes is correlated with IFN scores, and IFNα enhances caspase 1 expression via IFN regulatory factor 1 (Figure ).…”

Dp2-Induced Autoantigen/Autoantibody Production From Patients With Systemic Lupus Erythematosus Is Done Through AIM2 And Not NLRP3

“…Recently enhanced inflammasome activity in SLE has been previously reported [1]. A broad range of microbial, host and environmental triggers of inflammasome have been reported.…”