Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) leading to CNS inflammation and neurodegeneration. Current anti-inflammatory drugs have only limited efficacy on progressive neurodegenerative processes underlining the need to understand immune-mediated neuronal injury. Cell adhesion molecules play an important role for immune cell migration over the blood-brain barrier whereas their role in mediating potentially harmful contacts between invading immune cells and neurons is incompletely understood. Here, we assess the role of the CNS-specific neuronal adhesion molecule ICAM-5 using experimental autoimmune encephalomyelitis (EAE), an animal model of MS. ICAM-5 knockout mice show a more severe EAE disease course in the chronic phase indicating a neuroprotective function of ICAM-5 in progressive neurodegeneration. In agreement with the predominant CNS-specific function of ICAM-5, lymphocyte function-associated antigen 1 (LFA-1)/ICAM-1 contact between antigen-presenting cells and T helper (Th)17 cells in EAE is not affected by ICAM-5. Strikingly, intrathecal application of the shed soluble form, sICAM-5, ameliorates EAE disease symptoms and thus might serve locally as an endogenous neuronal defense mechanism which is activated upon neuroinflammation in the CNS. In humans, cerebrospinal fluid from patients suffering from progressive forms of MS shows decreased sICAM-5 levels, suggesting a lack of this endogenous protective pathway in these patient groups. Overall, our study points toward a novel role of ICAM-5 in CNS autoinflammation in progressive EAE/MS.
Highlights
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease which is characterized by T cells infiltrating the central nervous system (CNS), thereby initiating autoimmune neuroinflammation [1,2,3]
Since T helper 17 (Th17) cells play a major role in the immunopathology of both EAE and MS [22, 23], we first aimed to elucidate the influence of sICAM-5 on the interactions of this pathogenic T cell type with antigen-presenting cells (APCs)
There were no significant differences in the expression levels of lymphocyte function-associated antigen 1 (LFA-1) on either cell type (Figure 2A) indicating that T-cell differentiation and stimulation are independent of LFA-1 expression
Summary
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease which is characterized by T cells infiltrating the central nervous system (CNS), thereby initiating autoimmune neuroinflammation [1,2,3]. Adhesion molecules have been shown to be involved in direct T cell interactions with neurons in vivo, inducing cell-cell contact-mediated neuronal calcium elevations [6, 9, 10]. One prominent example is the intercellular adhesion molecule 1 (ICAM-1), which is typically expressed on endothelial and immune cells, and which can be induced by inflammatory cytokines such as interleukin (IL-1) and tumor necrosis factor (TNF). Leukocytes can bind to endothelial cells via lymphocyte functionassociated antigen 1 (LFA-1)/ ICAM-1 and transmigrate into CNS tissue [11]. A putative role of ICAM5 in neuroinflammation is of high interest as pharmacological targeting might address T cell-neuron contacts leading to T cell-mediated neuronal cell death. Encephalitis patients show elevated concentrations of sICAM-5 in the cerebrospinal fluid (CSF); its pathological relevance is still unclear [17]
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