Activation of inflammasomes in neural progenitor cells inhibits differentiation into neural cells

Abstract

[Introduction] Previous studies have suggested that neuroinflammation is an important factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's diseases or Parkinson's diseases. Activation of cytosolic protein complexes known as inflammasomes leads to the activation of pro-inflammtory cytokines such as IL-1beta or IL-18. Enhanced production of pro-inflammatory cytokines by sustained stimulation of inflammasomes in glial cells during neuroinflammation has been shown to result in severe neurodegeneration. Although adult neural regeneration (neurogenesis) after neural damage is carried out by proliferation and differentiation of neural progenitor cells (NPC), impairment of neurogenesis has been shown to contribute to cognitive decline in neurodegenerative diseases. In addition, it is recently found that stimulation with alpha-synuclein which is one of the etiologic factors in Parkinson's diseases activates inflammasomes in adult NPC. Thus, in the present study, we determined involvement of inflammasome activation on proliferation or differentiation of NPC. [Materials and Methods] The NPC were generated from mouse induced pluripotent stem cells (iPS cells) by the protocol published previously (Lee et al., Nat Biotechnol 2000). Activation of inflammasomes in NPC was examined by the expression of inflammasome components (NLRP3, ASC, or caspase-1), IL-1beta, or IL-18. Proliferation of NPC was examined by MTT assay. The differentiation potential of NPC into neural cells was evaluated by NeuN expression using immunofluorescence staining or western blot analysis. [Results] Treatment of mouse NPC with TNF (100 U/ml) significantly induced the expression of caspase-1, IL-1beta, and IL-18. The treatment with TNF (100 U/ml) also significantly inhibited NeuN expression in differentiated NPC. In addition, the simultaneous treatment with TNF and IL-1beta (0.3 ng/ml) significantly enhanced the inhibitory effect. Pretreatment with BAY11-7082 (an inhibitor of inflammasome activation; 10 microM) significantly reversed the effect of TNF. [Conclusion] These results suggest that the activation of inflammasomes in mouse NPC inhibits the differentiation into neural cells.