Toll-Like Receptors and Inflammation in the CNS

Abstract

The innate immune system recognizes "non-self" by employing a set of germline-encoded receptors called Toll-like receptors (TLRs), originally characterized in Drosophila. TLRs are involved in the recognition of various microbial-derived molecules, including lipopolysaccharide (LPS), lipoteichoic acid (LTA), and peptidoglycan (PGN), as well as unmethylated bacterial DNA. The TLR-mediated intracellular signaling pathways converge to activate nuclear factor-kappa B (NF-kappaB) and c-Jun N-terminal kinases (JNKs), which induce the transcription of a series of cytokine/chemokine genes that are involved in the initiation or regulation of the inflammatory response. It is now known that, like other peripheral organs, the central nervous system (CNS) is also under constitutive immune surveillance by CNS-resident glial cells (microglia and astrocytes) and CNS-infiltrating immune cells. The recent progress in our understanding of TLR functions in the innate immune response sheds new light on how inflammatory immune responses are initiated within the CNS. In this review, we discuss recent studies on TLRs and their ligands, signal transduction pathways activated by TLRs, and the mechanisms through which these various activation events occur. Finally, we discuss how TLRs might play similar important roles in CNS inflammation.

Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders

“…The signaling pathway leading to these varied activation states are controlled by the engagement of surface receptors by specific ligands (59, 60, 92–96). Our findings suggest that higher-ordered oligomeric α-synuclein is a DAMP that interacts with a specific TLR complex.…”

Therapeutic Developments Targeting Toll‐like Receptor‐4‐Mediated Neuroinflammation

“…Unlike TLRs of the immune system, these specific TLRs, especially TLR4, may release different kinds of signaling molecules after activation (Figure 1) [19] . Acting as macrophages in the nervous system, microglia may help to eradicate the damaged neural cells and invasive pathogen in the central nervous system (CNS) [16, 20] . On the other hand, release of signaling molecules at the end of the TLR signaling pathways would promote the inflammatory reaction inside the nervous system, which could result in neuralgia [21] .…”

Transient tactile allodynia following intrathecal puncture in mouse: Contributions of Toll-like receptor signaling

“…Interestingly the TLR pathway has been shown to play a role in post injury hyperpathia [9, 18, 21, 24]. Specifically, TLRs present on spinal microglia and astrocytes cells mediate this neuro-inflammatory response especially in the case of neuropathic injury possibly through the production of proinflammatory cytokines [3, 9, 14, 19, 25].…”