Abstract
Objective To reduce immune-mediated damage in a rat model of neuromyelitis optica (NMO) by blocking neutrophil migration using SCH527123, a drug that inhibits CXCR2. Background Neuromyelitis optica is a relapsing autoimmune disease that preferentially targets the optic nerves and spinal cord leading to blindness and paralysis. Part of the immunopathogenesis of this disease is thought to involve neutrophils, which are present within NMO lesions. We tested the effect of blocking neutrophil migration in an NMO rat model. Methods The Lewis rat model of NMO uses a myelin-reactive experimental autoimmune encephalomyelitis (EAE) background with passive transfer of pooled human antibody from patients with aquaporin-4 (AQP4) seropositive NMO at onset of EAE symptoms. We treated rats early in the course of EAE with CXCR2 inhibitor and assessed the extent of neutrophil infiltration into the spinal cord and the extent of AQP4 depletion. Results CXCR2 inhibitor decreased neutrophil migration into the spinal cord of AQP4 IgG-treated EAE rats. However, there was no difference in the acute behavioral signs of EAE or the extent and distribution of AQP4 lesions. This suggests that neutrophils are not centrally involved in the immunopathogenesis of the Lewis rat NMO disease model. Conclusions CXCR2 inhibitor blocks neutrophil migration into the spinal cord during EAE but does not significantly reduce inflammation or AQP4 lesions in the Lewis rat model of NMO.
Highlights
Neuromyelitis optica spectrum disorder (NMOSD) is a devastating autoimmune disease that targets the optic nerves and spinal cord leading to blindness and paralysis [1]
The pathology of NMOSD is distinguished from other demyelinating diseases, such as multiple sclerosis, by the presence of the aquaporin-4 (AQP4) serological antibody and by humorally mediated inflammatory markers associated with AQP4depleted lesions, including perivascular immunoglobulin and complement [2, 3]
Neutrophils and other granulocytes are present in lesions in the spinal cord and optic nerve where they have been speculated to contribute to the permanent destruction of the myelin, glial cells, and vulnerable neurons [4]
Summary
Neuromyelitis optica spectrum disorder (NMOSD) is a devastating autoimmune disease that targets the optic nerves and spinal cord leading to blindness and paralysis [1]. Neutrophils and other granulocytes are present in lesions in the spinal cord and optic nerve where they have been speculated to contribute to the permanent destruction of the myelin, glial cells, and vulnerable neurons [4]. Neutrophils have been identified as a key player in the effector pathway of NMO disease and are being targeted for intervention in clinical trials [5, 6]. Animal models of NMO demonstrated that neutrophils are important in lesion development; inhibition of neutrophils reduces the severity and size of lesions [7]. We tested the potential benefit of inhibiting neutrophil recruitment with a small molecular CXCR2 inhibitor, SCH527123, in a rat model of NMO. The purpose was to evaluate the impact of CXCR2 inhibition on the severity of immunemediated damage in the central nervous system
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