NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis

Abstract

Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). NLRP3 inflammasome activation is implicated in LN pathogenesis, suggesting its potential targets for LN treatment. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule that has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB)-mediated inflammatory responses in vivo. This molecule has also protective effects against the activation of the inflammasomes and, in particular, the NLRP3 inflammasome. Thus, this work evaluated the effect of melatonin on morphological alteration and NLRP3 inflammasome activation in LN pristane mouse models. To evaluate the melatonin effects in these mice, we studied the renal cytoarchitecture by means of morphological analyses and immunohistochemical expression of specific markers related to oxidative stress, inflammation and inflammasome activation. Our results showed that melatonin attenuates pristane-induced LN through restoring of morphology and attenuation of oxidative stress and inflammation through a pathway that inhibited activation of NLRP3 inflammasome signaling. Our data clearly demonstrate that melatonin has protective activity on lupus nephritis in these mice that is highly associated with its effect on enhancing the Nrf2 antioxidant signaling pathway and decreasing renal NLRP3 inflammasome activation.

Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling

“…Melatonin can protect against pristane-induced LN in mice, and this effect was attributed to its enhancing role on the Nrf2 signaling pathway and its ability to inhibit kidney NLRP3 inflammasome activation [144]. Also, obacunone and pyrroloquinoline quinone have shown promise in CKD for their antioxidant and anti-inflammatory potential [146,148].…”

Protective Role of Nrf2 in Renal Disease

“…In two different models of LN (B6.Sle1.Sle3 and MRL.lpr mice), bardoxolone methyl decreased glomerulonephritis by reducing the activity of the Mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 (MEK-1/2), ERK, and Signal transducer and activator of transcription 3 (STAT-3) signaling pathways and decreasing ROS production [ 230 ]. In this pathological context, melatonin and epigallocatechin-3-gallate increased Nrf2 expression and decreased the expression of the inflammatory NLRP3 signaling pathway [ 231 , 232 ]. In Nrf2-deficient B6/lpr mice, which are susceptible to LN, Th17 cell activation and STAT3 phosphorylation were increased, while the Th17 differentiation inhibitor SOCS3 (suppressor of cytokine signal 3) was decreased, indicating a protective role of Nrf2 in LN [ 233 ].…”

Melatonin attenuates AFB1-induced cardiotoxicity via the NLRP3 signalling pathway

“… 13 Melatonin's ability to inhibit activation of the NLRP3 inflammasome, due to its various antioxidant actions, has been fully documented in many experimental studies. 14 – 16 …”