期刊
ACTA NEUROPATHOLOGICA
卷 132, 期 3, 页码 413-431出版社
SPRINGER
DOI: 10.1007/s00401-016-1593-6
关键词
CNS autoimmunity; EAE; Farnesoid-X-receptor; Myeloid cells; IL-10
资金
- German Research Foundation [CRC 128 A8, CRC 128 Z1, CRC 128 Z2]
- Interdisciplinary center for clinical research (IZKF) [Kl2/015/14]
Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.
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