Elucidation of Relevant Neuroinflammation Mechanisms Using Gene Expression Profiling in Patients with Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by damage of motor neurons. Recent reports indicate that inflammatory responses occurring within the central nervous system contribute to the pathogenesis of ALS. We aimed to investigate disease-specific gene expression associated with neuroinflammation by conducting transcriptome analysis on fibroblasts from three patients with sporadic ALS and three normal controls. Several pathways were found to be upregulated in patients with ALS, among which the toll-like receptor (TLR) and NOD-like receptor (NLR) signaling pathways are related to the immune response. Genes—toll-interacting protein (TOLLIP), mitogen-activated protein kinase 9 (MAPK9), interleukin-1β (IL-1β), interleukin-8 (IL-8), and chemokine (C-X-C motif) ligand 1 (CXCL1)—related to these two pathways were validated using western blotting. This study validated the genes that are associated with TLR and NLR signaling pathways from different types of patient-derived cells. Not only fibroblasts but also induced pluripotent stem cells (iPSCs) and neural rosettes from the same origins showed similar expression patterns. Furthermore, expression of TOLLIP, a regulator of TLR signaling pathway, decreased with cellular aging as judged by changes in its expression through multiple passages. TOLLIP expression was downregulated in ALS cells under conditions of inflammation induced by lipopolysaccharide. Our data suggest that the TLR and NLR signaling pathways are involved in pathological innate immunity and neuroinflammation associated with ALS and that TOLLIP, MAPK9, IL-1β, IL-8, and CXCL1 play a role in ALS-specific immune responses. Moreover, changes of TOLLIP expression might be associated with progression of ALS.

Variability of the Expression Patterns of Neuroinflammatory Genes in Mononuclear Cells of Peripheral Blood in Amyotrophic Lateral Sclerosis

“…More and more studies point to the role of systemic inflammation and immune response in ALS patients [11][12][13]. It has been shown that in ALS, microglia and astrocytes are activated, which is neuroprotective in the early stages of the disease and proinflammatory in the later stages.…”

Neuronal Expression of UBQLN2P497H Exacerbates TDP-43 Pathology in TDP-43G348C Mice through Interaction with Ubiquitin

“…It is increased in serum and CSF of sALS patients [34]. CCL1 is secreted by the monocytes or macrophages in response to LPS exposure to promote the NF-κB pathway, and CXCL1 is also implicated in NF-κB activation through the PI3K/AKT signaling pathway and is also increased in ALS patient’s fibroblasts [35, 36]. We have previously reported that UBQLN2 up-regulation can activate the NF-κB signaling pathway [12].…”

Cromolyn sodium delays disease onset and is neuroprotective in the SOD1G93A Mouse Model of amyotrophic lateral sclerosis

“…CXCL1 is a chemotactic cytokine responsible for mediating migration of neutrophils to the site of inflammation 26–29 and previous studies have demonstrated a significant increase in CXCL1 levels in ALS 29,30 . Specifically, CXCL1 levels were increased in monocytes isolated from ALS patients 29 and in ALS patient-derived fibroblasts 30 . Here, we demonstrate that CXCL1 levels are increased in the spinal cord of TgSOD1 mice similar to previous reports in ALS patients, however, its role in ALS pathogenesis is yet unclear.…”