Dysregulation of chemokine receptor expression and function in leukocytes from ALS patients

Abstract

Amyotrophic lateral sclerosis (ALS) is rapidly progressive adult-onset motor neuron disease characterized by the neurodegeneration of both upper and lower motor neurons in the cortex and the spinal cord; the majority of patients succumb to respiratory failure. Although the etiology is not yet fully understood, there is compelling evidence that ALS is a multi-systemic disorder, with peripheral inflammation critically contributing to the disease process. However, the full extent and nature of this immunological dysregulation remains to be established, particularly within circulating blood cells. Therefore, the aim of the present study was to identify dysregulated inflammatory molecules in peripheral blood cells of ALS patients and analyze for functional consequences of the observed findings. To this end, we employed flow cytometry-based screening to quantify the surface expression of major chemokine receptors and integrins. A significantly increased expression of CXCR3, CXCR4, CCL2, and CCL5 was observed on T cells in ALS patients compared to healthy controls. Intriguingly, the expression was even more pronounced in patients with a slow progressive phenotype. To further investigate the functional consequences of this altered surface expression, we used a modified Boyden chamber assay to measure chemotaxis in ALS patient-derived lymphocytes. Interestingly, chemoattraction with the CXCR3-Ligand IP10 led to upregulated migratory behavior of ALS lymphocytes compared to healthy controls. Taken together, our data provides evidence for a functional dysregulation of IP10-directed chemotaxis in peripheral blood cells in ALS patients. However, whether the chemokine itself or its receptor CXCR3, or both, could serve as potential therapeutic targets in ALS requires further investigations.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1135-3) contains supplementary material, which is available to authorized users.

Plasma VCAM1 levels correlate with disease severity in Parkinson’s disease

“…Multicolor flow cytometry was used to determine the expression of selected inflammatory mediators (Fig. 1a) on the surface of B cells (CD19+), T cells (CD3+), NK cells (CD56+), NK-T cells (CD56+/CD3+), and classical monocytes (CD14+/CD16−) [4]. Cellular migration was assessed using a modified Boyden chamber assay with 100 ng/ml SDF-1α as a chemoattractant [4].…”

Bidirectional Microglia–Neuron Communication in Health and Disease

“…The receptor for CCL2 is found in microglia and its activation trigger chemotaxis of cultured microglia. An induction of neuronal CCL2 expression was described in response to various types of injury and degeneration such as ischemia, Alzheimer’s disease, MS, axonal injury, amyotrophic lateral sclerosis (ALS) or peripheral nerve injury ( Barna et al, 1994 ; Che et al, 2001 ; Pang et al, 2001 ; Rancan et al, 2001 ; Schreiber et al, 2001 ; Baron et al, 2005 ; Bose and Cho, 2013 ; Perner et al, 2018 ). The chemokine CCL2 is also produced by glial cells ( Barna et al, 1994 ; Hanisch, 2002 ; He et al, 2016 ) as perivascular astrocytes have been identified as the most common and predominant source of CCL2 in the CNS in various neuroinflammatory conditions ( Andjelkovic et al, 2002 ; Guillemin et al, 2003 ).…”

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

“…The expression of MCP-1 receptor (CCR2) is reduced on circulating monocytes in ALS (146). Another study showed significantly increased expression of CXCR3, CXCR4, CCL2, and CCL5 on T lymphocytes in ALS patients compared to healthy controls (147). There are higher levels of the chemokine MCP-1 in patients with a shorter diagnostic delay, which is a marker of more severe rapidly progressing disease (148).…”