TLR8: An Innate Immune Receptor in Brain, Neurons and Axons

Abstract

AbbReViATionSIκBα nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α IRAK interleukin-1 receptor-associated kinase LPS lipopolysaccharide MyD88 myeloid differentiation factor 88 NFκB nuclear factor-κB PAMPs pathogen-associated molecular patterns TLR Toll-like receptor AcKnowLedgeMenTSWe thank colleagues I. Chiu, J. Lu, and J. Sloane for critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health and the National Multiple Sclerosis Society. AbSTRAcTToll-like receptors (TLRs) play essential roles in generating innate immune responses, and are evolutionarily conserved across species. In mammals, TLRs specifically recognize the conserved microbial structural motifs referred to as pathogen-associated molecular patterns (PAMPs). Ligand recognition by TLRs activates signaling cascades that culminate in proinflammatory cytokine production and eventual elimination of invading pathogens. Although TLRs in mammals are expressed predominantly in the immune system, certain TLRs with poorly characterized function are also found in neurons. We recently profiled TLR8 expression during mouse brain development and established its localization in neurons and axons. We uncovered a novel role for TLR8 as a suppressor of neurite outgrowth as well as an inducer of neuronal apoptosis, and found that TLR8 functions in neurons through an NFκB-independent mechanism. These findings add a new layer of complexity for TLR signaling, and expand the realm of mammalian TLR function to the central nervous system (CNS) beyond the originally discovered immune context. Herein, we complement our earlier report with additional data, discuss their biological and mechanistic implications in CNS developmental and pathological processes, and thus further our perspective on TLR signaling and potential physiological roles in mammals.

Immune and Nervous Systems: More Than Just a Superficial Similarity?

“…Thus, cells in the CNS appear to be activated via TLR8 by ligands that are not of bacterial origin but that are induced during injury, autoimmune situations, hypoxia, and neurodegeneration (Kielian, 2006;Ma et al, 2007). Moreover, TLR8 stimulation has been associated with suppression of neurite outgrowth and induction of apoptosis.…”

MR Imaging for Diagnostic Evaluation of Encephalopathy in the Newborn

“…MR imaging features of human parechovirus include punctate high-signal-intensity white matter lesions on T1-weighted images and symmetric foci of restricted diffusion in the subcortical white matter, corpus callosum, optic radiation, internal capsule, and cerebral peduncles on diffusion-weighted images (30) (Fig 25). In the presence of a parechovirus infection, inflammatory cytokines that are toxic to premyelinating oligodendrocytes and developing axons may be secreted by microglia (31).…”

Mechanisms and Patterns of Axonal Loss in Multiple Sclerosis

“…Neurological deficits manifest clinically in EAE mice at approximately the same time as characteristic SMI32+ spheroids are detectable in spinal cord axons ( Figure 6, Soulika et al, 2009). These spheroids contain high concentrations of Toll-like receptor 8 (TLR8) protein (Soulika et al, 2009) shown to cause neuronal death via apoptosis and inhibit neurite formation (Ma et al, 2006(Ma et al, , 2007. In this same EAE model, innate immunity infiltrates are detectable early on in the disease course.…”