Activation of Innate Immune response by HERV-K/HML-2 Envelope via interactions with TLR2 in Amyotrophic Lateral Sclerosis
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Endogenous Retroviruses (ERVs) comprise a significant fraction of mammalian genomes and are thought to contribute to human disease, including neurological disorders and neurodegenerative diseases. Previous studies have identified upregulation of the human endogenous retrovirus-K (HERV-K) subtype HML-2 envelope in sporadic amyotrophic lateral sclerosis (sALS) and demonstrated direct neuronal toxicity in in-vitro and in animal models. Additionally, individuals with ALS have distinct proinflammatory cytokine profiles in the cerebrospinal fluid (CSF), suggesting alternate forms of immune activation depending on underlying molecular drivers. Of the innate immune receptors, toll-like receptors (TLRs) are upregulated in ALS patients, but the potential triggers are unknown. In this study, we explored the potential role of HERV-K Env in mediating innate immune activation. We first identified TLR-2/6/7/10 as dysregulated in the motor cortex by analysis of RNA-Seq data from the New York Genome Center (NYGC) ALS Consortium. We then confirmed the up-regulation of TLR-2 in the pre-motor region in cortical tissues from ALS donors, age and sex-matched to controls. To investigate TLR-2 expression in tissue, we conducted immunohistochemistry in a transgenic (Tg) murine model with the HERV-K env as the transgene and observed cell-type specific alterations in TLR2 expression.We exposed resting primary monocyte-derived macrophages (MDMs) to Envelope protein derived from biologically relevant chromosomal loci. We discovered that HERV-K Env can dose-dependently activate the macrophage conical NF-KappaB pathway post-exposure, leading to IL-6 and TNF-a proinflammatory cytokine secretion. To explore potential co-receptors involved in TLR-2 signaling, we used an established TLR-2 expressing cell line and treated it with the Envelope protein in the presence or absence of selective inhibitors MMG11 (TLR-2/1) and Cu-CPT22 (TLR-2/6, TLR2/1). The findings suggest TLR-2/6 may be used by Envelope to trigger inflammation. To determine the essential need for TLR2, we utilized an established Null-HEK-Blue cell line to confirm the requirement for TLR2 in Env-induced NF-KappaB activation. Lastly, we identify a humoral abnormality in ALS patients that leads to lower titers of HERV-K Envelope protein in plasma and serum. Our work represents the first study demonstrating that an endogenous retroviral envelope protein can trigger an innate immune response. This finding suggests that targeting TLR-2 could be a novel approach to abating immune activation in ALS while arguing for the use of retroviral elements in identifying and stratifying neurodegenerative disorders.
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