Myelin-phagocytosing macrophages modulate autoreactive T cell proliferation
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JOURNAL OF NEUROINFLAMMATION
RESEARCH
Open Access
Myelin-phagocytosing macrophages modulate autoreactive T cell proliferation Jeroen FJ Bogie, Piet Stinissen, Niels Hellings and Jerome JA Hendriks*
Abstract Introduction: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) in which macrophages play a central role. Initially, macrophages where thought to be merely detrimental in MS, however, recent evidence suggests that their functional phenotype is altered following myelin phagocytosis. Macrophages that have phagocytosed myelin may be less inflammatory and may exert beneficial effects. The presence of myelin-containing macrophages in CNS-draining lymph nodes and perivascular spaces of MS patients suggests that these cells are ideally positioned to exert an immune regulatory role. Therefore we evaluated in this study the effect of myelin-phagocytosing macrophages on lymphocyte reactivity. Methods: Thioglycolate-elicited rat peritoneal macrophages were loaded with myelin and cocultured with myelinbasic protein (MBP) or ovalbumin (OVA) reactive lymphocytes. Lymphocyte proliferation was determined by CFSElabeling. The role of nitric oxide in regulating lymphocyte proliferation was assessed by addition of an inhibitor of inducible nitric oxide synthase to the coculture. In vivo immune regulation was investigated by treating MBP- and OVA-immunized animals subcutaneously with myelin. Cognate antigen specific lymphocyte proliferation and nitric oxide production were determined 9d post-immunization. Results: In this study we demonstrate that myelin-phagocytosing macrophages inhibit TCR-triggered lymphocyte proliferation in an antigen-independent manner. The observed immune suppression is mediated by an increase in NO production by myelin-phagocytosing macrophages upon contact with lymphocytes. Additionally, myelin delivery to primarily CD169+ macrophages in popliteal lymph nodes of OVA-immunized animals results in a reduced cognate antigen specific proliferation. In contrast to OVA-immunized animals, lymphocytes from MBPimmunized animals displayed an increased proliferation after stimulation with their cognate antigen, indicating that myelin-phagocytosing macrophages have dual effects depending on the specificity of surrounding lymphocytes. Conclusions: Collectively our data show that myelin phagocytosis leads to an altered macrophage function that inhibits lymphocyte proliferation. Additionally, results from this study indicate that myelin-phagocytosing macrophages fulfill a dual role in vivo. On one hand they aggravate autoimmunity by activating myelin-reactive lymphocytes and on the other hand they suppress lymphocyte reactivity by producing NO.
Introduction Multiple Sclerosis (MS) is characterized as a chronic, inflammatory, neurodegenerative disease of the central nervous system (CNS). It is regarded to be an autoimmune disease as activated autoimmune lymphocytes are pivotal in orchestrating the immunopathological processes involved in myelin sheath damage
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