Toll-like receptors in neurodegeneration

Abstract

The key roles of toll-like receptors (TLRs) as mediators of the detection and responses of immune cells to invading pathogens are well known. There are at least 13 mammalian TLRs which are integral membrane proteins with a leucine-rich extracellular domain and a cytoplasmic domain similar to that of the interleukin-1 receptor which initiates downstream signaling through kinases to activate transcription factors such as AP-1 and NFkappaB. TLRs are activated in glial cells (microglia, astrocytes and oligodendrocytes) and lymphocytes that infiltrate the nervous system in response to inflammation caused by infectious agents, tissue injury or autoimmune conditions. By inducing the production of pro-inflammatory cytokines and cell adhesion molecules in immune cells, TLRs may indirectly damage neurons in conditions such as ischemic stroke and multiple sclerosis. Recent findings suggest that neurons also express a subset of TLRs and that their activation promotes neuronal degeneration in experimental models of stroke and Alzheimer's disease. TLRs may also play roles in regulating the processes of neurogenesis and neurite outgrowth, suggesting roles in neuronal plasticity. A better understanding of the molecular and cellular biology of TLRs in the normal and diseased nervous system, may lead to novel approaches for preventing neuronal degeneration and promoting recovery of function in an array of neurodegenerative conditions.

Figure 1

TLR mediated signaling. (a) The Myd88 mediated pathway is shared by all the TLRs with the exception of TLR3. MyD88 recruits TRAF6 and members of the IRAK family. TRAF6, along with Uev1A and Ubc13 activates the TAK1 complex by a K63 linked ubiquitination. The TAK1 complex then activates the IKK complex that consists of IKKα, IKKβ and IKKγ, that further catalyzes IκB proteins phosphorylation. This in turn facilitates IκB proteins degradation by a proteasome-dependent manner, which allows NFκB translocation to the nucleus. In parallel to activating the IKK complex, TAK1 activates the MAPK pathway which culminates in AP-1 activation. The combination of AP-1 and NFκB controls inflammatory responses mediated by inflammatory cytokines. (b) The MyD88 independent pathway initiates when TRIF associates with TRAF3 which binds to TBK1 and IKKε. This binding culminates in IRF3 phosphorylation that facilitates IRF3 dimerization and translocation into the nucleus and transcription regulation. TRIF can also interact with TRAF6 which along with RIP1 mediates NFκB activation. TRIF can also induce IRF2 translocation to the nucleus and transcription through the PI3K-AKT pathway.

Figure 2

The roles of TLR signaling in glial cells, endothelial cells, leukocytes and neuronal cells during the pathogenesis of ischemic stroke. During ischemic stroke, TLRs are activated and induce NFκB activation in glial cells, endothelial cells and infiltrating lymphocytes. In neurons, the JNK/AP-1 pathway is activated. This culminates in proinflammatory cytokines and chemokines secretion, nitric oxide synthase and cox-2 expression induction. Endothelial cells dysfunction causes blood-brain-barrier permeability which promotes further lipid peroxidation, apoptosis of neurons, infarct and neurological deficits as the final outcome.