Manganese induces neuroinflammation via NF-κB/ROS NLRP3 pathway in rat brain striatum and HAPI cells

다국어 초록 (Multilingual Abstract)

Backgrounds: Chronic exposure to excessive Mn can result in neurodegenerative symptoms, whose precise molecular mechanism remains largely unclear. Here, we measured the role and mechanism of NLRP3 in Mninduced neuroinflammation in vivo and vitro.
Methods: The effects of Mn on NLRP3 activation were investigated by Westernblot, IHC, immunofluorescence analysis, as well as ELISA. We assessed NF-κB activation through measurement of phosphorylation and nuclear translocation. The mechanisms bywhich Mn induced NLRP3 activation were assessed by specific inhibitors.
Results: We found that Mn exposure facilitated the activation of NLRP3 inflammasome to promote the production of IL-1β and IL-18 in dose- and time-dependent manners in HAPI cells. In addition, the NLRP3 inflammasome was also dramatically activated in microglia of rat brain striatum after Mn exposure. We also found increased ROS and NF-κB activation. Notably, the activation of NLRP3 was significantly attenuated by pretreatment with NF-κB and ROS inhibitors.
Conclusion: These findings suggest that NLRP3 activation plays an important role in Mn-induced neuroinflammation, and it is associated with NF-κB and ROS.

참고문헌 (Reference)

1 Jiang, J. K., "Upregulation of mitochondrial protease HtrA2/Omi contributes to manganese-induced neuronal apoptosis in rat brain striatum" 268 : 169-179, 2014

2 Peres, T. V., "Tyrosine hydroxylase regulation in adult rat striatum following short-term neonatal exposure to manganese" 8 : 597-604, 2016

3 Arlehamn, C. S., "The role of potassium in inflammasome activation by bacteria" 285 : 10508-10518, 2010

4 Wang, D., "The role of NLRP3-CASP1 in inflammasome-mediated neuroinflammation and autophagy dysfunction in manganese-induced, hippocampal-dependent impairment of learning and memory ability" 13 : 914-927, 2017

5 Schwartz, M., "The resolution of neuroinflammation in neurodegeneration : leukocyte recruitment via the choroid plexus" 33 : 7-22, 2014

6 Martinon, F., "The inflammasome : a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta" 10 : 417-426, 2002

7 Tan, M. S., "The NLRP3 inflammasome in Alzheimer’s disease" 48 : 875-882, 2013

8 Ozaki, E., "Targeting the NLRP3 inflammasome in chronic inflammatory diseases : current perspectives" 8 : 15-27, 2015

9 Liccione, J. J., "Selective vulnerability of glutathione metabolism and cellular defense mechanisms in rat striatum to manganese" 247 : 156-161, 1988

10 Alfonso-Loeches, S., "Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells" 8 : 216-, 2014

11 Mizushima, H., "Reduced postischemic apoptosis in the hippocampus of mice deficient in interleukin-1" 448 : 203-216, 2002

12 Cai, Q., "Polysaccharides from Ganoderma lucidum attenuate microglia-mediated neuroinflammation and modulate microglial phagocytosis and behavioural response" 14 : 63-, 2017

13 Wan, C., "Pivotal roles of p53 transcription-dependent and-independent pathways in manganese-induced mitochondrial dysfunction and neuronal apoptosis" 281 : 294-302, 2014

14 Gustin, A., "NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes" 10 : e0130624-, 2015

15 Shao, B. Z., "NLRP3 inflammasome and its inhibitors : a review" 6 : 262-, 2015

16 Tschopp, J., "NLRP3 inflammasome activation:The convergence of multiple signalling pathways on ROS production?" 10 : 210-215, 2010

17 De Lucia, C., "Microglia regulate hippocampal neurogenesis during chronic neurodegeneration" 55 : 179-190, 2016

18 Hines, D. J., "Microglia processes block the spread of damage in the brain and require functional chloride channels" 57 : 1610-1618, 2009

19 He, Y., "Mechanism and regulation of NLRP3 inflammasome activation" 41 : 1012-1021, 2016

20 Peres, T. V., "Manganese-induced neurotoxicity : a review of its behavioral consequences and neuroprotective strategies" 17 : 57-, 2016

21 Gawlik, M., "Manganese neurotoxicity and protective effects of resveratrol and quercetin in preclinical research" 69 : 322-330, 2017

22 Zhao, F., "Manganese induces dopaminergic neurodegeneration via microglial activation in a rat model of manganism" 107 : 156-164, 2009

23 Yin, L., "Manganese exposure facilitates microglial JAK2-STAT3 signaling and consequent secretion of TNF-a and IL-1beta to promote neuronal death" 64 : 195-203, 2017

24 Bjorklund, G., "Manganese exposure and neurotoxic effects in children" 155 : 380-384, 2017

25 Bouabid, S., "Manganese Neurotoxicity : behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission" 136 : 677-691, 2015

26 Shi, S., "KHSRP participates in manganese-induced neurotoxicity in rat striatum and PC12 cells" 55 : 454-465, 2015

27 Tanaka, S., "Involvement of interleukin-1 in lipopolysaccaride-induced microglial activation and learning and memory deficits" 89 : 506-514, 2011

28 Alam, Q., "Inflammatory process in Alzheimer’s and Parkinson’s diseases : central role of cytokines" 22 : 541-548, 2016

29 Kim, E. H., "Increased expression of the NLRP3 inflammasome components in patients with Behcet’s disease" 12 : 41-, 2015

30 Murphy, N., "Glial uptake of amyloid beta induces NLRP3 inflammasome formation via cathepsin-dependent degradation of NLRP10" 16 : 205-215, 2014

31 Shan, H., "Fluoxetine protects against IL-1beta-induced neuronal apoptosis via downregulation of p53" 107 : 68-78, 2016

32 Jiang, J., "Downregulation of the Wnt/beta-catenin signaling pathway is involved in manganese-induced neurotoxicity in rat striatum and PC12 cells" 92 : 783-794, 2014

33 Wu, Z., "Differential pathways for interleukin-1beta production activated by chromogranin A and amyloid beta in microglia" 34 : 2715-2725, 2013

34 Hornung, V., "Critical functions of priming and lysosomal damage for NLRP3 activation" 40 : 620-623, 2010

35 Tanaka, S., "Activation of microglia induces symptoms of Parkinson’s disease in wild-type, but not in IL-1 knockout mice" 10 : 143-, 2013

36 Piccini, A., "ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1beta and IL-18 secretion in an autocrine way" 105 : 8067-8072, 2008

37 Zhou, R., "A role for mitochondria in NLRP3 inflammasome activation" 469 : 221-225, 2011