Neutrophils Amplify Autoimmune Central Nervous System Infiltrates by Maturing Local APCs

Abstract

Multiple sclerosis is considered to be initiated by a deregulated, myelin-specific T cell response. However, the formation of inflammatory CNS lesions and the contribution of different leukocyte subsets in setting up these lesions are still incompletely understood. In this study, we show that, in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, neutrophil granulocytes are important contributors in preparing CNS inflammation. Preclinical single-dose Ab-mediated depletion of neutrophils delayed the onset and continuous depletion attenuated the development of experimental autoimmune encephalomyelitis, whereas the generation of a myelin-specific T cell response remained unaffected. Neutrophil-related enzymes such as myeloperoxidase and neutrophil elastase did not contribute in mounting CNS inflammation, as analyzed by using respective knockout mice and inhibitors. CNS-infiltrating neutrophils secreted proinflammatory molecules and matured bone marrow–derived dendritic cells in vitro, which in turn enhanced their ability to restimulate myelin-specific T cells. This was mirrored in vivo, in which depletion of neutrophils specifically impaired maturation of microglia and macrophages into professional APCs, resulting in a diminished amplification of early CNS inflammation. Therefore, inside the CNS neutrophils provide local cofactors that are required for the maturation of myeloid cells into professional APCs representing an essential step for the local restimulation of myelin-specific T cells and the development of autoimmune disease.

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

“…At 7 d.p.i., Ly6G + neutrophils were significantly more numerous than CD3 + T cells, whereas both cell types were present at similar levels at 14 and 21 d.p.i. Taken together, these results support other studies pointing toward an early involvement of neutrophils in CNS pathophysiology (15,16,18,27), as they infiltrate the spinal cord parenchyma during the preclinical stage of EAE, consistent with our intravital imaging data (Fig. 1A-C).…”

“…denced by their conspicuous presence in early inflammatory infiltrates (17,18,27,74). In keeping with these data, we show that GFP + neutrophils are present in the spinal cord of lys-eGFP-ki mice 1 d prior to the manifestation of clinical symptoms, before transiently infiltrating the parenchyma.…”

“…In the present study, we demonstrate that these infiltrated GFP + cells are majorly composed of neutrophils and that their depletion leads to a marked decrease of vascular leakage in EAE mice as compared with control animals. Moreover, and in accordance with previous reports, we found the severity of the disease to be reduced in neutrophildepleted animals (16,27,32). Finally, immunohistochemical analysis of tissue sections from MS brain and NMO spinal cord reveals that neutrophils are closely apposed to the CNS vasculature, in areas associated with increased BBB/BSCB leakage.…”

“…PMNs are also increasingly recognized as having pivotal functions in driving inflammatory processes within the target organ, extending their role beyond that of bystander cells of the adaptive immune response (19)(20)(21). Recent findings present neutrophils as potent modulators of dendritic cell recruitment and function, which themselves are responsible for Ag presentation to encephalitogenic Th1 and Th17 cells following the latter's transmigration from the perivascular space into the parenchyma (22)(23)(24)(25)(26)(27). The activity of IFN-g-producing Th1 lymphocytes is suppressed by neutrophils in the CNS of EAE mice, and neutrophilderived myeloperoxidase was shown to inhibit dendritic cell activation, therefore dampening T cell-driven inflammation (28,29).…”

T cell mediated pathogenesis in EAE: Molecular mechanisms

“…[79] Other target cells of IL-17 in the CNS may be the NG2-expressing oligodendrocyte precursor cells. Deletion of the IL-17 signaling molecule ACT1 in these cells was shown to have a major impact on EAE.…”