Chapter 12: Manganese and Neuroinflammation

Neurotoxicity due to excessive exposure to manganese (Mn) has been described as early as 1837. Despite extensive study over the past century, it is only now becoming clear that Mn neurotoxicity involves complex pathophysiological signaling mechanisms between neurons and glial cells. Glial cells are an important target of Mn in the brain, where high levels of the metal accumulate, activating inflammatory signaling pathways that damage neurons through overproduction of numerous reactive oxygen and nitrogen species and inflammatory cytokines. Understanding how these pathways are regulated in glial cells during Mn exposure is critical to determining the mechanisms underlying permanent neurological dysfunction stemming from excess exposure. Neuroinflammatory activation of glial cells is an important mechanism in Mn neurotoxicity and in other degenerative conditions of the central nervous system. Recent studies have redefined the importance of astrocytes and microglia to neuronal development, homeostasis, and survival, transforming our understanding of the role of these cells from inert structural components to important components of brain physiology and pathology. This chapter will describe the role of microglia and astrocytes in the neurotoxicity of Mn and outline how Mn-dependent neuroinflammatory signaling mechanisms are regulated at a molecular level in these cell types. In addition, methods for studying interactions between glial cell types will also be discussed in context of deciphering which inflammatory signaling molecules are critical to neuronal injury during Mn exposure.