Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential

Abstract

The discovery of mammalian TLRs (Toll-like receptors), first identified in 1997 based on their homology with Drosophila Toll, greatly altered our understanding of how the innate immune system recognizes and responds to diverse microbial pathogens. TLRs are evolutionarily conserved type I transmembrane proteins expressed in both immune and non-immune cells, and are typified by N-terminal leucine-rich repeats and a highly conserved C-terminal domain termed the TIR [Toll/interleukin (IL)-1 receptor] domain. Upon stimulation with their cognate ligands, TLR signalling elicits the production of cytokines, enzymes and other inflammatory mediators that can have an impact on several aspects of CNS (central nervous system) homoeostasis and pathology. For example, TLR signalling plays a crucial role in initiating host defence responses during CNS microbial infection. Furthermore, TLRs are targets for many adjuvants which help shape pathogen-specific adaptive immune responses in addition to triggering innate immunity. Our knowledge of TLR expression and function in the CNS has greatly expanded over the last decade, with new data revealing that TLRs also have an impact on non-infectious CNS diseases/injury. In particular, TLRs recognize a number of endogenous molecules liberated from damaged tissues and, as such, influence inflammatory responses during tissue injury and autoimmunity. In addition, recent studies have implicated TLR involvement during neurogenesis, and learning and memory in the absence of any underlying infectious aetiology. Owing to their presence and immune-regulatory role within the brain, TLRs represent an attractive therapeutic target for numerous CNS disorders and infectious diseases. However, it is clear that TLRs can exert either beneficial or detrimental effects in the CNS, which probably depend on the context of tissue homoeostasis or pathology. Therefore any potential therapeutic manipulation of TLRs will require an understanding of the signals governing specific CNS disorders to achieve tailored therapy.

Figure 1. Toll-like receptor (TLR) localization and signaling

TLR1, TLR2, TLR4, TLR5, and TLR6 are expressed at the cell surface for extracellular ligand recognition whereas TLR3, TLR7, and TLR9 are localized in the endosomal compartment for the recognition of pathogen nucleic acid motifs. All TLRs, with the exception of TLR3, recruit MyD88, while TLR1, TLR2, TLR4 and TLR6 recruit the additional adaptors CD14 and TIRAP, the latter of which links the TIR domain with MyD88. In the MyD88-dependent pathway, MyD88 recruits the IRAK family of proteins which leads to I-κB phosphorylation, resulting in the release and nuclear translocation of NF-κB, which influences the expression of numerous inflammatory genes. TLR3 ligands initiate the TRIF-dependent pathway, whereas TLR4 can signal via either MyD88-dependent or TRIF-dependent pathways requiring the additional linker adaptor TRAM, which links the TIR domain of TLR4 with TRIF. In the TRIF-dependent pathway, TRIF interacts with TRAF3 to activate IRF3 and IRF7 and initiate type I interferon production. Alternatively, TRIF can also bind to RIP1 and TRAF6 and activate NF-κB and MAPK for late-phase (i.e. 24 h) induction of inflammatory gene expression.

Figure 2. Expression of TLR family members in CNS cells

Microglia express all TLRs identified to date, whereas astrocytes, oligodendrocytes and neurons express a more limited TLR repertoire in comparison.