A Clear and Present Danger: Endogenous Ligands of Toll-like Receptors

Abstract

Neurologic disease promoted by microbial pathogens, sterile injury, or neurodegeneration rapidly induces innate immunity in adjacent healthy tissue, which in turn contributes extensively to neurologic injury. With more recent focus on innate immune processes, it appears that necrotic, but not apoptotic, death mechanisms provoke inflammatory responses likely due to the release or production of endogenous ligands that activate resident immune cells of the central nervous system. These ligands comprise a diverse set of proteins, nucleic acids, and gly-cosaminoglycans, including heat shock proteins, HMGB1, RNA, DNA, hyaluronan, and heparin sulfate, that stimulate innate immune mechanisms largely through Toll-like receptors (TLRs). The blockade of interactions between endogenous ligands and TLRs may enable neuroprotective therapeutic strategies for a variety of neurologic diseases.

Effect of TNF-α inhibitors on transcriptional levels of pro-inflammatory interleukin-33 and Toll-like receptors-2 and -9 in psoriatic plaques

“…Each TLR is activated by a different microbial component, although they trigger a common myeloid differentiation factor 88 (MyD88)-dependent pathway, leading, via nuclear factor (NF)-κB, to the production of pro-inflammatory cytokines and chemokines, such as TNF-α (12). TLR-2 is a type of TLR that is highly expressed in keratinocytes, and Langerhans and mast cells of psoriatic plaques (14)(15)(16) and is activated by various microorganism antigens (17)(18)(19)(20) or endogenous heat-shock proteins present at sites of tissue injury and inflammation (21). TLR-9 is another type of TLR that has been observed to be elevated in the keratinocytes of psoriatic skin lesions (22) and is activated by unmethylated DNA sequences (CpG dinucleotides) that are present in bacterial DNA and viruses (17).…”

Influence of Extracellular RNAs, Released by Rheumatoid Arthritis Synovial Fibroblasts, on Their Adhesive and Invasive Properties

“…exRNA, in association with microparticles or exosomes, can be released by cell death or actively by vital cells, especially under hypoxia (1,10,12,13,16,17), in which case the underlying release mechanisms are unclear. The released exRNA is stabilized by binding to proteins or to cell surface molecules (9,17) and may thus be resistant against degradation by RNases (13).…”

Mechanisms and Patterns of Axonal Loss in Multiple Sclerosis

“…Brain cells are capable of releasing endogenous ligands in response to cellular damage which activate innate and cellular immune responses (Matzinger, 2002;Sloane et al, 2010a). Recent evidence shows that, in an EAE mouse model, axonal dystrophy can occur in prelesion areas before hits of inflammatory demyelination (About-Enein et al, 2006;Nikić et al, 2011).…”