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Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool


In multiple sclerosis and the experimental autoimmune encephalitis (EAE) mouse model, two pools of morphologically indistinguishable phagocytic cells, microglia and inflammatory macrophages, accrue from proliferating resident precursors and recruitment of blood-borne progenitors, respectively. Whether these cell types are functionally equivalent is hotly debated, but is challenging to address experimentally. Using a combination of parabiosis and myeloablation to replace circulating progenitors without affecting CNS-resident microglia, we found a strong correlation between monocyte infiltration and progression to the paralytic stage of EAE. Inhibition of chemokine receptor–dependent recruitment of monocytes to the CNS blocked EAE progression, suggesting that these infiltrating cells are essential for pathogenesis. Finally, we found that, although microglia can enter the cell cycle and return to quiescence following remission, recruited monocytes vanish, and therefore do not ultimately contribute to the resident microglial pool. In conclusion, we identified two distinct subsets of myelomonocytic cells with distinct roles in neuroinflammation and disease progression.

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Figure 1: Irradiation and separation of parabiotic mice leads to peripheral blood chimerism in the absence of donor cell entry into the CNS.
Figure 2: Monocytic infiltration correlates with progression to paralytic stages of EAE.
Figure 3: Blood-derived infiltrating cells retain monocyte characteristics during progression to paralytic disease.
Figure 4: Kinetics of microglia expansion and blood-derived monocyte infiltration in EAE.
Figure 5: Blocking monocyte infiltration prevents EAE progression.
Figure 6: Blood-borne inflammatory cell infiltration is transient.
Figure 7: Uncommitted stem or progenitor cells, but not myelomonocytic-committed hematopoietic progenitors, contribute to resident microglia in irradiated-transplanted recipients.


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We thank B. Chua, T. Godbey, K. Ranta, M. Cowan, L. Rollins and the Biomedical Research Center animal unit personnel for advice and help on animal welfare. We thank A. Johnson, C.K. Chang, J. Kang and D. Mahdaviani for their technical help. This work was supported by Canadian Institute for Health Research (CIHR, MOP 81382) grants and a grant from the Multiple Sclerosis Society of Canada to F.M.V.R., a Neuromuscular Research Partnership grant from the CIHR, a grant from the Amyotrophic Lateral Sclerosis Society of Canada and Muscular Dystrophy Canada to C.K. and F.M.V.R. (JNM-69682), a Collaborative Health Research grant from the CIHR and the Natural Science and Engineering Research Council of Canada to C.K. and F.M.V.R. (CHRP 299119), and a research grant from the Multiple Sclerosis Society of Canada to K.M.M. K.M.M. is a Michael Smith Foundation for Health Research Senior Scholar. B.A is supported by a Michael Smith Foundation Senior Graduate Studentship and a CIHR–Amyotrophic Lateral Sclerosis Doctoral Research Award. J.L.B. is supported by a Multiple Sclerosis Society of Canada Postdoctoral Research Fellowship. This research was undertaken, in part, thanks to funding from the Canadian Research Chairs program to F.M.V.R.

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B.A. designed and conducted all of the experiments, interpreted the data and wrote the manuscript. J.L.B. conducted the EAE induction and participated in the writing of the manuscript. C.K. and K.M.M. participated in the writing of the manuscript. F.M.V.R. designed and interpreted experiments and wrote the manuscript.

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Correspondence to Fabio M V Rossi.

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The authors declare no competing financial interests.

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Ajami, B., Bennett, J., Krieger, C. et al. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14, 1142–1149 (2011).

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