Neutrophil protease inhibition reduces neuromyelitis optica–immunoglobulin G–induced damage in mouse brain

Abstract

Objective Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with pathogenic autoantibodies against the astrocyte water channel protein aquaporin-4 (AQP4). The presence of neutrophils is a characteristic feature in NMO lesions in humans. Neutrophils are not generally found in multiple sclerosis lesions. We evaluated the role of neutrophils in a mouse NMO model. Methods NMO lesions were produced in mice by intracerebral injection of immunoglobulin G (IgG) isolated from NMO patient serum and human complement. We previously reported that this mouse model produces the characteristic histological features of NMO, including perivascular complement activation, inflammatory cell infiltration, and loss of myelin, AQP4, and glial fibrillary acidic protein. Lesions are absent when AQP4 null mice are used or when IgG from non-NMO patients is injected. Results We found remarkably reduced neuroinflammation, myelin loss, and AQP4 loss in brains of neutropenic mice at 24 hours and 7 days, and increased severity of NMO lesions in mice made neutrophilic by granulocyte colony stimulating factor. NMO lesions were greatly reduced by intracerebral administration of the neutrophil protease inhibitors Sivelestat and cathepsin G inhibitor I or by intraperitoneal injection of Sivelestat alone. Immunostaining of human NMO lesions for neutrophil elastase revealed many degranulating perivascular neutrophils, with no equivalent perivascular neutrophils in human multiple sclerosis lesions. Interpretation Our data implicate a central role of neutrophils in the pathogenesis of early NMO lesions and suggest the potential utility of neutrophil protease inhibitors such as Sivelestat in NMO therapy.

Neutrophils Amplify Autoimmune Central Nervous System Infiltrates by Maturing Local APCs

“…4B). Although inhibition of ELANE has been reported to ameliorate Th17-induced adoptive transfer EAE (24) and a mouse model of neuromyelitis optica (25), treatment with both inhibitors did not alter the development of actively induced EAE, indicating that both enzymes are not critically involved in neutrophil recruitment and effector function necessary for the development of actively induced EAE. Among other neutrophilproduced proinflammatory soluble factors, cytokines are good candidates as early signals setting up an inflammatory milieu.…”

Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica

“…Prior passive-transfer mouse models of NMO involving intracerebral brain injection of NMO-IgG and complement produced NMO-like pathology, but without eosinophil infiltration (19,20). After testing multiple variations of existing models, including eotaxin and IL-5 infusion together with NMO-IgG and complement administration, we found that human-like NMO pathology could be produced by 3-day continuous intracerebral infusion of NMO-IgG and hc ( Figure 4A).…”

“…We reported recently that neutrophils and neutrophil elastase exacerbate NMO pathology in spinal cord slice cultures exposed to NMO-IgG and complement, and that the neutrophil elastase inhibitor Sivelestat largely prevented the neutrophil-dependent pathology (15). NMO pathology was greatly exacerbated in neutrophilic mice administered NMO-IgG and complement by intraparenchymal injection, and was reduced in neutropenic mice or in normal mice treated with neutrophil elastase inhibitors (20). A recent case report described rapid clinical deterioration in an NMO patient made neutrophilic by inadvertent administration of G-CSF (27).…”

“…Figure 5B shows reduced lesion size and eosinophil infiltration in the anti-IL-5 antibody-treated mice. In a second set of studies, in order to isolate the effects of eosinophils versus neutrophils, we compared NMO lesions produced by NMOIgG and complement in mice made neutropenic with anti-Ly6G antibody (20), without versus with anti-IL-5 antibody treatment. Treatment with anti-Ly6G antibody significantly reduced lesion size, which was further reduced by anti-IL-5 treatment ( Figure 5C).…”

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

“…Cinryze therapy was safe and associated with disability improvement to preattack levels in 9/10 patients after 1 month. Finally, inhibition of neutrophil elastase with sivelestat was beneficial in animal models of NMOSD [55,56], and a small open-label trial evaluating sivelestat for NMOSD attacks is currently being conducted in Japan.…”