Immune cell trafficking from the brain maintains CNS immune tolerance
Mohammad G. Mohammad, Vicky W.W. Tsai, Marc J. Ruitenberg, Masoud Hassanpour, Hui Li, Prue H. Hart, Samuel N. Breit, Paul E. Sawchenko, David A. Brown
Mohammad G. Mohammad, Vicky W.W. Tsai, Marc J. Ruitenberg, Masoud Hassanpour, Hui Li, Prue H. Hart, Samuel N. Breit, Paul E. Sawchenko, David A. Brown
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Research Article

Immune cell trafficking from the brain maintains CNS immune tolerance

Abstract

In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.

Authors

Mohammad G. Mohammad, Vicky W.W. Tsai, Marc J. Ruitenberg, Masoud Hassanpour, Hui Li, Prue H. Hart, Samuel N. Breit, Paul E. Sawchenko, David A. Brown

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Figure 5

CD11c+ cells are recruited to the proximal RMS and travel to the OB, and RMS disruptions leads to their accumulation.

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CD11c+ cells are recruited to the proximal RMS and travel to the OB, and...
(A) With i.p. fingolimod treatment (n = 5), the frequency of CD11c+ cells in the proximal RMS (RMSO) remained unchanged. However, the CD11c+ cell density significantly increased in the terminal field of the RMS (P = 0.042) and was further enriched in the ventral part of the OB (VOB; P = 0.014). (B) Representative sections of the ventral OB showing accumulated CD11c+ cells in fingolimod-treated mice compared with vehicle controls. (C) CFSE-labeled BMDCs were given icv (n = 3/group). CFSE+ cells (green) were present in the proximal-mid RMS (DCX, red) at 16 hours (top), and by 24 hours (bottom) had reached the OB. (D) The RMS was ablated with a 7-day icv ARA-c infusion. There were significantly fewer CD11c+ DCs in the proximal region of the ablated RMS (P = 0.04, n = 3/group). (E) However, in similarly treated mice, FACS analysis of CNS mononuclear cells from the forebrain showed significantly increased macrophages and DCs, similar to systemic fingolimod treatment (P = 0.03, n = 6; 2 independent experiments). (F) Representative FACS plots showing CFSE-labeled DCs that had migrated from CNS to CxLNs isolated 48 hours from mice after 3 icv injections of fingolimod-pretreated (100 nM for 24 hours), CFSE-labeled BMDCs (1 × 106 cells/injection) at 12-hour intervals (n = 7/group, 2 independent experiments). (G) Fingolimod treatment of DCs significantly reduced their migration into CxLNs (P = 0.042, n = 7; 2 independent experiments). Scale bars: 100 μm; 10 μm (insets). Data represent mean ± SEM. *P < 0.05.