Abstract
The chaperone protein Unc-93 homolog B1 (UNC93B1) regulates internalization, trafficking, and stabilization of nucleic acid-sensing Toll-like receptors (TLR) in peripheral immune cells. We sought to determine UNC93B1 expression and its functional relevance in inflammatory and injurious processes in the central nervous system (CNS). We found that UNC93B1 is expressed in various CNS cells including microglia, astrocytes, oligodendrocytes, and neurons, as assessed by PCR, immunocyto-/histochemistry, and flow cytometry. UNC93B1 expression in the murine brain increased during development. Exposure to the microRNA let-7b, a recently discovered endogenous TLR7 activator, but also to TLR3 and TLR4 agonists, led to increased UNC93B1 expression in microglia and neurons. Microglial activation by extracellular let-7b required functional UNC93B1, as assessed by TNF ELISA. Neuronal injury induced by extracellular let-7b was dependent on UNC93B1, as UNC93B1-deficient neurons were unaffected by the microRNA’s neurotoxicity in vitro. Intrathecal application of let-7b triggered neurodegeneration in wild-type mice, whereas mice deficient for UNC93B1 were protected against injurious effects on neurons and axons. In summary, our data demonstrate broad UNC93B1 expression in the murine brain and establish this chaperone as a modulator of neuroinflammation and neuronal injury triggered by extracellular microRNA and subsequent induction of TLR signaling.
Highlights
Toll-like receptors (TLRs) are pattern recognition receptors that mediate innate immune cell signaling in response to both pathogen- and host-derived molecules [1]
We first analyzed different enriched central nervous system (CNS) cell types such as microglia, astrocytes, and neurons, as well as whole brain tissue derived from C57BL/6 mice regarding Unc93b1 mRNA expression by end-point PCR
Unc93b1 RNA was readily detectable in WT whole brain, its expression signal comparable to that in lung and liver tissue, but at lower level compared to spleen tissue
Summary
Toll-like receptors (TLRs) are pattern recognition receptors that mediate innate immune cell signaling in response to both pathogen- and host-derived molecules [1]. UNC93B1 is an endoplasmic reticulum (ER)-resident transmembrane protein that controls TLR trafficking from the ER in peripheral immune cells, such as bone-marrow-derived macrophages and dendritic cells [7, 8]. This chaperone binds to TLR3, TLR7, and TLR9 in the ER and traffics with them to their appropriate intracellular locations where they are subsequently available to sense their cognate ligands [9, 10]. UNC93B1 stabilizes TLR proteins and prevents their degradation, functions that are independent of its endosomal trafficking activity [11]. The importance of UNC93B1 in NA recognition and host defense is emphasized by the development of Herpes simplex virus type 1 encephalitis in human patients lacking functional UNC93B1 [13]
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