The role of NLRP3-CASP1 in inflammasome-mediated neuroinflammation and autophagy dysfunction in manganese-induced, hippocampal-dependent impairment of learning and memory ability

Abstract

Central nervous system (CNS) inflammation and autophagy dysfunction are known to be involved in the pathology of neurodegenerative diseases. Manganese (Mn), a neurotoxic metal, has the potential to induce microglia-mediated neuroinflammation as well as autophagy dysfunction. NLRP3 (NLR family, pyrin domain containing 3)-CASP1 (caspase 1) inflammasome-mediated neuroinflammation in microglia has specific relevance to neurological diseases. However, the mechanism driving these phenomena remains poorly understood. We demonstrate that Mn activates the NLRP3-CASP1 inflammasome pathway in the hippocampus of mice and BV2 cells by triggering autophagy-lysosomal dysfunction. The autophagylysosomal dysfunction is induced by lysosomal damage caused by excessive Mn accumulation, damaging the structure and normal function of these organelles. Additionally, we show that the release of lysosomal CTSB (cathepsin B) plays an important role in Mn-induced NLRP3-CASP1 inflammasome activation, and that the increased autophagosomes in the cytoplasm are not the main cause of NLRP3-CASP1 inflammasome activation. The accumulation of proinflammatory cytokines, such as IL1B (interleukin 1 b) and IL18 (interleukin 18), as well as the dysfunctional autophagy pathway may damage hippocampal neuronal cells, thus leading to hippocampal-dependent impairment in learning and memory, which is associated with the pathogenesis of Alzheimer disease (AD).

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

“…Neuroinflammation occurs as a response in the central nervous system (CNS) to neuronal injury . Many studies have indicated that neuroinflammation results in diverse neurological disorders, including neurodegenerative diseases, traumatic brain injury, and neurotoxicity induced by heavy metals . As the abundant cells in the CNS, astrocytes exhibit a wide range of functions in maintaining brain homeostasis.…”

“…17 Many studies have indicated that neuroinflammation results in diverse neurological disorders, including neurodegenerative diseases, 18,19 traumatic brain injury, 20 and neurotoxicity induced by heavy metals. 21,22 As the abundant cells in the CNS, astrocytes exhibit a wide range of functions in maintaining brain homeostasis. Given that astrocytes detect noxious signals and respond by secreting inflammatory mediators, they are recognized as crucial regulators of the inflammatory response to injury of the CNS.…”

Activation of G protein‐coupled receptor 30 protects neurons by regulating autophagy in astrocytes

“…Excitotoxicity and neuroinflammation are intimately linked to autophagic dysfunction (Ginet et al, 2014;Wang et al, 2017;Yang et al, 2017). In the peripheral nervous system, autophagy prevented inflammation and autophagic inhibition promoted inflammation-induced tissue injury (Kimura, Isaka, & Yoshimori, 2017;Macias-Ceja et al, 2017).…”

The Effect of Thermal Therapy on Uremic Pruritus in Hemodialysis Patients

“…The stimulation of the sympathetic nervous system affects the uremic pruritus (20). Moreover, infrared electromagnetic waves of FIR are effective in stimulating inflammatory suppressor (21). They are used for pain relief, burn repair, tumor growth retardation, and stimulation of macrophage function (21,22).…”

“…Moreover, infrared electromagnetic waves of FIR are effective in stimulating inflammatory suppressor (21). They are used for pain relief, burn repair, tumor growth retardation, and stimulation of macrophage function (21,22). However, molecular mechanisms by which they cause FIR function are still unclear (23).…”