There is currently no evidence that LPS or bacterial infection contribute directly to the pathogenesis of PD in humans. However, the emerging recognition of the roles of TLRs in a number of inflammatory diseases raises the possibility that endogenous TLR ligands are generated during aging that contribute to disease initiation or progression. For example, components of dying cells, such as Hsp60, have been shown to trigger TLR4 activity (Lehnardt et al., 2008). Other factors, such as ATP, can also induce inflammatory responses through other signaling pathways (Di Virgilio, 2007). A transient event leading to neuronal injury could thus lead to activation of microglia, with subsequent amplification of inflammation by astrocytes. The present findings suggest that Nurr1 protects the CNS from amplification of inflammatory signaling by microglia-astrocyte communication. Strategies to suppress expression of neurotoxins either directly or by interfering with microglia/astrocyte communication may thus have therapeutic utility. Furthermore, it may be necessary to suppress the production of neurotoxic mediators by microglia and astrocytes in order to obtain reconstitution of functional neuronal circuits using cell-based therapies (Brundin et al., 2008).
