Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs

TY - JOUR

T1 - Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs

AU - Steinbach, Karin

AU - Piedavent, Melanie

AU - Bauer, Simone

AU - Neumann, Johannes T

AU - Friese, Manuel A

PY - 2013/11/1

Y1 - 2013/11/1

N2 - 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.

AB - 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.

KW - Animals

KW - Antigen Presentation

KW - Antigen-Presenting Cells

KW - Autoimmunity

KW - Cells, Cultured

KW - Central Nervous System

KW - Cytokines

KW - Dendritic Cells

KW - Encephalomyelitis, Autoimmune, Experimental

KW - Inflammation

KW - Leukocyte Elastase

KW - Macrophages

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Microglia

KW - Multiple Sclerosis

KW - Neutrophils

KW - Peroxidase

KW - T-Lymphocytes

U2 - 10.4049/jimmunol.1202613

DO - 10.4049/jimmunol.1202613

M3 - SCORING: Journal article

C2 - 24062488

VL - 191

SP - 4531

EP - 4539

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 9

ER -