Abstract
BackgroundThe activation of NOD-like receptor protein 3 (NLRP3) inflammasome-dependent pyroptosis has been shown to play a vital role in the pathology of manganese (Mn)-induced neurotoxicity. Sodium para-aminosalicylic acid (PAS-Na) has a positive effect on the treatment of manganism. However, the mechanism is still unclear. We hypothesized that PAS-Na might act through NLRP3.MethodsThe microglial cell line BV2 and male Sprague-Dawley rats were used to investigate the impacts of PAS-Na on Mn-induced NLRP3 inflammasome-dependent pyroptosis. The related protein of the NF-κB pathway and NLRP3-inflammasome-dependent pyroptosis was detected by western blot. The reactive oxygen species and mitochondrial membrane potential were detected by immunofluorescence staining and flow cytometry. The activation of microglia and the gasdermin D (GSDMD) were detected by immunofluorescence staining.ResultsOur results showed that Mn treatment induced oxidative stress and activated the NF-κB pathway by increasing the phosphorylation of p65 and IkB-α in BV2 cells and in the basal ganglia of rats. PAS-Na could alleviate Mn-induced oxidative stress damage by inhibiting ROS generation, increasing mitochondrial membrane potential and ATP levels, thereby reducing the phosphorylation of p65 and IkB-α. Besides, Mn treatment could activate the NLRP3 pathway and promote the secretion of IL-18 and IL-1β, mediating pyroptosis in BV2 cells and in the basal ganglia and hippocampus of rats. But an inhibitor of NF-κb (JSH-23) treatment could significantly reduce LDH release, the expression of NLRP3 and Cleaved CASP1 protein and IL-1β and IL-18 mRNA level in BV2 cells. Interestingly, the effect of PAS-Na treatment in Mn-treated BV2 cells is similar to those of JSH-23. Besides, immunofluorescence results showed that PAS-Na reduced the increase number of activated microglia, which stained positively for GSDMD.ConclusionPAS-Na antagonized Mn-induced NLRP3 inflammasome dependent pyroptosis through inhibiting NF-κB pathway activation and oxidative stress.
Highlights
Manganese (Mn) is one of the occupational and environmental toxicants, it is an essential trace element for normal physiological functions [1]
We find that Mn can trigger neurotoxicity by oxidative stress, NF-κB pathway activation and NOD-like receptor protein 3 (NLRP3) inflammasome-dependent pyroptosis
Our previous study showed that Mn levels in the striatum and globus pallidus of rats were dramatically increased after 15 mg/kg MnCl2 treatment for 3 weeks compared to the control group (1.53 ± 0.04 vs 0.92 ± 0.02 and 1.47 ± 0.03 vs 0.87 ± 0.07, respectively) [48]
Summary
Manganese (Mn) is one of the occupational and environmental toxicants, it is an essential trace element for normal physiological functions [1]. The primary innate immune monitors in the central nervous system (CNS), make up 10–15% of nerve cells in the CNS under normal conditions [10]. It is primarily involved in maintaining the normal homeostasis of CNS by producing anti-inflammatory and neurotropic factors etc. Once environmental exotoxins excessively activate microglia, the balance between its protection and pro-inflammatory effects is interrupted [12]. Excessive Mn exposure or its combination with lipopolysaccharide (LPS) may induce the activation of microglial cells, which causes neuroinflammation via promoting the secretion of cytotoxic mediators, such as interleukin-1β (IL-1β) and reactive oxygen species (ROS) [13, 14].
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