Neuroinflammatory responses may be dependent on the initiation of innate immune responses triggered by the stimulation of intrinsic brain cells by pathogen-associated molecular patterns (PAMPs), repeated structural motifs generated by microbes that are not normally found in the host or by debris from apoptotic or necrotic cells following injury. One group of receptors that recognize viral PAMPs is the toll-like receptor (TLR) 9 family, which is composed of TLR7, TLR8 and TLR9. These receptors form a closely related family that are highly homologous, confined to the endosomal membranes and recognize nucleic acids that are encountered in these compartments. TLR7 and TLR8 recognize single stranded RNA (ssRNA) from a number of virus families, while TLR9 recognizes unmethylated DNA containing CpG motifs (CpG DNA). There are several recent studies demonstrating that TLR9 family members play an important role in neuropathogenesis, including our study demonstrating that TLR7 plays a role in retrovirus-induced innate immune responses in the central nervous system (CNS). Additionally, TLR7 and TLR9 agonists are being studied as potential therapeutics for multiple diseases in the brain, ranging from virus infections to the treatment of brain tumors. However, there is a lack of basic understanding of which cell types in the brain respond to stimulation of TLRs, as well as the pathways of neuroinflammation, neuroprotection and/or neuronal damage induced when these TLRs are activated. Understanding the similarities and differences of TLR7, TLR8 and TLR9-induced cell activation in the brain is important for understanding viral pathogenesis as well as potential use of TLR agonists in the treatment of neurological diseases. Our laboratory has focused on understanding the response of intrinsic brain cells following TLR activation and determining the downstream effects of TLR activation on neuroinflammation and neuropathogenesis. In FY2011, we analyzed the neuroinflammatory response to TLR7 and TLR9 in the developing CNS. TLR9, but not TLR7, stimulation in the CNS induced damage to the brain and clinical disease at higher doses. Further analysis revealed that TLR9 signaling lead to very strong cytokine responses in the CNS, the breakdown of the blood-CSF barrier and infiltration of inflammatory cells into the brain. The cell type that appears to trigger this response was found to be choroid plexus cells, indicating that these cells can play an important role in mediating neuroinflammatory responses particularly in the developing brain. In addition to these studies, we analyzed the potential for murine TLR8 to contribute to neuroinflammation. The role of murine TLR8 in mediating innate immune responses has been controversial, but multiple papers have suggested that it may play a role in mediating neuronal death. In addition, recent studies have suggested that murine TLR8 is activated by alternative ligands (primarily repetitive oligonucleotides). We examined the role of murine TLR8 using conventional and alternative ligands. We found that murine TLR8 was not activated by either type of ligand and did not play a substantial role in the activation of glial cells or in the induction of type I IFN or cytokines by glial cells.
Showing the most recent 10 out of 14 publications
