Mult Scler. Author manuscript; available in PMC 2012 April 5.
Abstract
Background
The pathology of neuromyelitis optica (NMO), in contrast to multiple sclerosis, comprises granulocyte infiltrates along extensive lengths of spinal cord, as well as optic nerve. Furthermore, IFN-β treatment worsens NMO. We recently found that experimental autoimmune encephalomyelitis (EAE) induced with Th17 cells is exacerbated by IFN-β, in contrast to disease induced with Th1 where treatment attenuated symptoms.
Objective
This study demonstrates the similarities between NMO and Th17 EAE and how neutrophils mediate pathology in Th17 disease.
Methods
Levels of blood biomarkers in NMO were assessed by Luminex and ELISA. Effects of IFN-β on neutrophils were assessed by culture assays and immunofluorescence. EAE was induced by transfer of myelin-specific Th1 orTh17 cells and treated with Sivelestat sodium hydrate, a neutrophil elastase inhibitor.
Results
We show Th17 cytokines, granulocyte chemokines, type I interferon and neutrophil elastase are elevated in patients with definitive NMO. In culture, we find that IFN-β stimulates neutrophils to release neutrophil elastase. In Th17 EAE, we demonstrate neutrophilic infiltration in the optic nerve and spinal cord which was not present in Th1 EAE. Blockade of neutrophil elastase with Sivelestat had efficacy in Th17 EAE but not Th1 EAE.
Conclusions
The similarities between Th17 EAE and NMO indicate that this model represents several aspects of NMO. Neutrophils are critical in the pathologies of both Th17-EAE and NMO, and therefore blockade of neutrophil elastase is a promising target in treating NMO.
Introduction
Neuromyelitis optica (NMO) and relapsing-remitting multiple sclerosis (RRMS) are both neuro-inflammatory diseases that lead to central nervous system (CNS) demyelination.1 NMO is characterized by the presence of severe inflammation in the optic nerves and spinal cord,1 and lesions are also found in the brain in 60–70% of patients.2,3 In addition, approximately 80% of patients with NMO develop auto-antibodies against Aquaporin 4 (AQP4), and the presence of AQP4-lg is one clinical feature that is used to distinguish NMO from RRMS.4
One feature of the inflammatory cells that comprise NMO lesions is the presence of granulocytes, which are largely absent in RRMS lesions.1 In NMO, IL-17 and IL-8 are elevated in the cerebrospinal fluid (CSF) compared with RRMS.5,6 In addition, the frequency of Th17 cells in the blood is elevated in NMO compared with RRMS.7 IL-17 signaling is known to upregulate chemokines that recruit and activate granulocytes, such as IL-8, G-CSF and Gro-α.8–10 The popular treatment for RRMS, beta-interferon (IFN-β), worsens NMO, increasing relapses and levels of AQP4 antibodies.11–14 We recently found that Th17-induced demyelination was exacerbated after IFN-β treatment.15 Overall, these data suggest that NMO is driven by the Th17 pathway, and that treatment with type 1 interferon exacerbates Th17-mediated disease.
In this study, we show that the signature of cytokines and chemokines and the cytopathology in the CNS are similar inpatients with NMO and in mice with Th17-induced experimental autoimmune encephalomyelitis (EAE). We also demonstrate that inhibition of neutrophil elastase is effective in attenuating Th17-induced EAE. This finding implies that granulocyte enzymes are critical in the pathology of Th17 inflammatory CNS disease, and suggests that inhibition of neutrophil elastase could be a therapeutic strategy to treat acute relapses in NMO.
Continued at resource.