Induction of the type I interferon response in neurological forms of Gaucher disease

Vitner et al. Journal of Neuroinflammation (2016) 13:104 DOI 10.1186/s12974-016-0570-2 RESEARCH Open Access Induction of the type I interferon response in neurological forms of Gaucher disease Einat B. Vitner1,5†, Tamar Farfel-Becker1,6†, Natalia Santos Ferreira1, Dena Leshkowitz2, Piyush Sharma3, Karl S. Lang3,4 and Anthony H. Futerman1* Abstract Background: Neuroinflammation is a key phenomenon in the pathogenesis of many neurodegenerative diseases. Understanding the mechanisms by which brain inflammation is engaged and delineating the key players in the immune response and their contribution to brain pathology is of great importance for the identification of novel therapeutic targets for these devastating diseases. Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the GBA1 gene and is a significant risk factor for Parkinson’s disease; in some forms of Gaucher disease, neuroinflammation is observed. Methods: An unbiased gene profile analysis was performed on a severely affected brain area of a neurological form of a Gaucher disease mouse at a pre-symptomatic stage; the mouse used for this study, the Gbaflox/flox; nestin-Cre mouse, was engineered such that GBA1 deficiency is restricted to cells of neuronal lineage, i.e., neurons and macroglia. Results: The 10 most up-regulated genes in the ventral posteromedial/posterolateral region of the thalamus were inflammatory genes, with the gene expression signature significantly enriched in interferon signaling genes. Interferon β levels were elevated in neurons, and interferon-stimulated genes were elevated mainly in microglia. Interferon signaling pathways were elevated to a small extent in the brain of another lysosomal storage disease mouse model, Krabbe disease, but not in Niemann-Pick C or Sandhoff mouse brain. Ablation of the type I interferon receptor attenuated neuroinflammation but had no effect on GD mouse viability. Conclusions: Our results imply that the type I interferon response is involved in the development of nGD pathology, and possibly in other lysosomal storage diseases in which simple glycosphingolipids accumulate, and support the notion that interferon signaling pathways play a vital role in the sterile inflammation that often occurs during chronic neurodegenerative diseases in which neuroinflammation is present. Background Type I interferons (IFNs; Ifnα1-13 and Ifnβ), a large family of structurally related cytokines, are key components of the innate immune response and are the fundamental cellular defense mechanism against viral infection [1]. IFNs are currently used therapeutically for a number of viral diseases, for numerous malignancies, and for a number of chronic inflammatory disorders such as the demyelinating disease and multiple sclerosis [2]. However, even though activation of the type 1 IFN response has been intensely * Correspondence: † Equal contributors 1 Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel Full list of author information is available at the end of the article studied as part of the host response to viral and bacterial infection, induction of this response has also been observed in the absence of infection [3]. In the central nervous system (CNS), IFN activation occurs in amyotrophic lateral sclerosis (ALS) [4], in Alzheimer’s disease (AD) [5], during aging [6], in Aicardi-Goutières syndrome (AGS) [7, 8], and upon axonal transection [9]. Activation of the IFN response under sterile conditions has led to a paradigm shift in our understanding of the role of these cytokines and their role in inflammation inasmuch as the type I interferonopathies are now believed to comprise a heterogeneous group of genetically determined diseases characterized by inappropriate activation of the type I IFN response [10]. © 2016 Vitner et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Vitner et al. Journal of Neuroinflammation (2016) 13:104 A wide range of neurodegenerative conditions are characterized by brain inflammation, including Alzheimer’s and Parkinson’s diseases (PD) [11], and the less common lysosomal storage diseases (LSDs) [12–14], which are normally caused by the defective activity of a lysosomal hydrolase. One such LSD is Gaucher disease (GD), caused by mutations in the GBA1 gene, which encodes the lysosomal enzyme, acid-β-glucosidase (glucocerebrosidase, GCase) [15], resulting in the accumulation of the sphingolipid glucosylceramide (GlcCer) and its deacylated form, glucosylsphingosine (GlcSph) [16, 17]. GD is the most common LSD and ~10 % of GD patients worldwide present with neurological symptoms. However, the distinction between neurological and non-neurological forms of the disease has become blurred over the recent years based on the finding that heterozygous mutations in GBA1 are a major risk factor for PD [18]. Thus, understanding the pathological pathways activated upon alteration of GCase activity in the brain might have significant ramifications for understanding more common neurodegenerative diseases such as PD. The neuronopathic forms of GD, types 2 and 3, are characterized by astrogliosis, neuronophagia (i.e., brain inflammation), and neuronal loss [19, 20]. We now demonstrate elevation of IFNβ levels in neurons and activation of the type 1 IFN response in mouse models of neuronopathic Gaucher disease (nGD), but to a much lower extent, or absent completely, in other LSD mouse models. This discovery was made during an unbiased gene profile analysis of a severely affected brain area of an nGD mouse at a pre-symptomatic stage. The mouse used for this study, the Gbaflox/flox; nestin-Cre mouse [21], was engineered such that GBA1 deficiency is restricted to cells of neuronal lineage, i.e., neurons and macroglia. Robust induction of type I IFN-stimulated genes (ISGs), including pathogen recognition receptors (PRRs) and antiviral genes was observed; the lack of activation of this pathway in other LSDs suggests that GlcCer and/or GlcSph specifically activate the antiviral response. Moreover, our data suggest that a key player in the pathway of programmed necrosis, the protein mixed lineage kinase domain-like (MLKL), is a novel ISG which is induced down-stream to the IFN receptor in cells of myeloid lineage. Together, our data demonstrate that the IFN response can be activated in neuroinflammation under sterile conditions and that this pathway might be involved (...truncated)