Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation

Abstract

IntroductionLupus nephritis (LN) is a major complication of systemic lupus erythematosus. NLRP3 inflammasome activation, reactive oxygen species (ROS) and mononuclear leukocyte infiltration in the kidney have been shown to provoke the acceleration and deterioration of LN, such as accelerated and severe LN (ASLN). Development of a novel therapeutic remedy based on these molecular events to prevent the progression of the disease is clinically warranted.MethodsCitral (3,7-dimethyl-2,6-octadienal), a major active compound in a Chinese herbal medicine Litsea cubeba, was used to test its renoprotective effects in a lipopolysaccharide (LPS)-induced mouse ASLN model by examining NLRP3 inflammasome activation, ROS and COX-2 production as well as Nrf2 activation. The analysis of mechanisms of action of Citral also involved its effects on IL-1β secretion and signaling pathways of NLRP3 inflammasome in LPS-primed peritoneal macrophages or J774A macrophages.ResultsAttenuated proteinuria, renal function impairment, and renal histopathology, the latter including intrinsic cell proliferation, cellular crescents, neutrophil influx, fibrinoid necrosis in the glomerulus, and peri-glomerular infiltration of mononuclear leukocytes as well as glomerulonephritis activity score were observed in Citral-treated ASLN mice. In addition, Citral inhibited NLRP3 inflammasome activation and levels of ROS, NAD(P)H oxidase subunit p47phox, or COX-2, and it enhanced the activation of nuclear factor E2-related factor 2 (Nrf2). In LPS-primed macrophages, Citral reduced ATP-induced IL-1β secretion and caspase-1 activation, but did not affect LPS-induced NLRP3 protein expression.ConclusionOur data show that Citral alleviates the mouse ASLN model by inhibition of the activation signal, but not the priming signal, of NLRP3 inflammasome and enhanced activation of Nrf2 antioxidant signaling.

NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy

“…Mouse peritoneal macrophages48, BMDCs47, and glomerular PMCs49 were prepared from NLRP3 KO and WT mice as described previously. All cells were cultured at 37 °C in a 5% CO 2 incubator.…”

The Parenchyma of Secondary Xylem and Its Critical Role in Tree Defense against Fungal Decay in Relation to the CODIT Model

“…White rot is further divided into two broad divisions: selective delignification ( Figure 3E ) and simultaneous rot. The former degrades lignin preferentially prior to hemicellulose and cellulose, using a range of oxidative enzymes, including laccase, tyrosinase and peroxidase (Schwarze et al, 2000c; Schwarze, 2008), while the latter degrades both lignin and cellulose together at approximately equal rates, where all substances of the cell wall are digested (Liese, 1970). In contrast to the brown rot, white rot fungi of the selective delignification type are able to destroy the cell walls of RAP (and possibly ‘living’ fibers) with ease during the early stages of delignification, whereas the fibers (libriform) are left intact.…”

“…The spread pattern of white rot fungi occurs via enzymes and direct hyphal penetration either through intercellular pits or through boreholes. The boreholes (also known to occur in brown rots) are small cavities formed in the cell walls and are caused by specialized cell-wall degrading hyphae (Bayliss, 1908; Nutman, 1929; Liese and Schmid, 1966; Liese, 1970; Schwarze et al, 2000a). Certain species of fungi, such as I. hispidus and Meripilus giganteus use RP cells effectively to breach the reaction zones of wall 3 ( Figure 3D ).…”

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

“…The best characterized inflammasome is one which contains the nucleotide-binding oligomerization domain (NOD)-like receptor 3 (NLRP3), the adapter molecule apoptosis-associated speck-like protein that contains a CARD (ASC), and caspase-1. This inflammasome complex is hyper-activated in lupus macrophages(2), is activated by lupus-specific autoantibodies(1, 6, 7), and contributes to the development of nephritis(11, 12). …”