Abstract
Toll-like receptors (TLRs) belong to pattern recognition receptors, which respond to danger signals such as pathogen-associated molecular patterns or damage-associated molecular patterns. Upon TLR activation in microglia, the major immune cells in the brain, distinct signaling cascades trigger the production of inflammatory molecules, being a critical feature in neuroinflammation and neurodegenerative processes. Recently, individual microRNAs (miRNAs) were shown to act as endogenous TLR ligands. Here, we conducted systematic screening for miRNAs as potential TLR7/8 ligands by small RNA sequencing of apoptotic neurons and their corresponding supernatants. Several miRNA species were identified in both supernatants and injured neurons, and 83.3% of the media-enriched miRNAs activated murine and/or human TLR7/8 expressed in HEK293-derived TLR reporter cells. Among the detected extracellular miRNAs, distinct miRNAs such as miR-340-3p and miR-132-5p induced cytokine and chemokine release from microglia and triggered neurotoxicity in vitro. Taken together, our systematic study establishes miRNAs released from injured neurons as new TLR7/8 activators, which contribute to inflammatory and neurodegenerative responses in the central nervous system (CNS).
Highlights
Toll-like receptors (TLRs) belong to a family of pattern recognition receptors, which recognize pathogen-associated molecules, such as bacterial and viral components, and damage-associated molecules derived from necrotic cells and tumor tissue
To identify further miRNAs that are able to activate nucleic-acid sensing TLRs in the central nervous system (CNS) within a systematic approach, apoptosis was induced in murine primary cortical neurons by staurosporine, an established bacterial toxin causing programed cell death in neurons [14,15,16,17] (Figure 1a)
Small RNAs present in the neuronal supernatants and the small RNA fraction derived from the apoptotic neurons were isolated
Summary
Toll-like receptors (TLRs) belong to a family of pattern recognition receptors, which recognize pathogen-associated molecules, such as bacterial and viral components, and damage-associated molecules derived from necrotic cells and tumor tissue. Two different classes of TLRs have been identified: the ones located at the cell surface, and TLRs such as TLR7 and TLR8 located in endosomes, mediating an inflammatory response against invading viruses and bacteria by sensing GU- and AU-rich single-stranded RNA (ssRNA) [3,4]. TLRs contain a ligand-sensing ectodomain composed of leucine-rich repeats (LRRs). They are anchored by a transmembrane domain, which is linked to a cytoplasmic Toll/IL-1 receptor (TIR) domain that allows for binding of specific adaptor proteins, thereby activating downstream cascades.
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