The cytokine transforming growth factor-β (TGF-β) regulates the development and homeostasis of several tissue-resident macrophage populations, including microglia. TGF-β is not critical for microglia survival but is required for the maintenance of the microglia-specific homeostatic gene signature1,2. Under defined host conditions, circulating monocytes can compete for the microglial niche and give rise to long-lived monocyte-derived macrophages residing in the central nervous system (CNS)3,4,5. Whether monocytes require TGF-β for colonization of the microglial niche and maintenance of CNS integrity is unknown. We found that abrogation of TGF-β signaling in CX3CR1+ monocyte-derived macrophages led to rapid onset of a progressive and fatal demyelinating motor disease characterized by myelin-laden giant macrophages throughout the spinal cord. Tgfbr2-deficient macrophages were characterized by high expression of genes encoding proteins involved in antigen presentation, inflammation and phagocytosis. TGF-β is thus crucial for the functional integration of monocytes into the CNS microenvironment.
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We thank A. van Vollenhoven for flow cytometry. We thank the staff at AKM, particularly E. Qvist, for animal caretaking and M. Gustafsson for performing tail-vein injections. We thank A. Svensson, D. Sunnemark and A. Dahlstrand for help with slide scanning, performed at Offspring Biosciences, Södertälje. We thank M. Li (Sloan Kettering Institute) for Tgfbr2fl/fl mice and F. Wermeling (Karolinska Institutet) for CD45.1 mice. We acknowledge support from the Science for Life Laboratory, the National Genomics Infrastructure (NGI) and Uppmax for providing assistance in next-generation sequencing and computational infrastructure.
This work was supported by grants from the Swedish Alzheimer Foundation (Alzheimerfonden, AF-74004, R.A.H.), Swedish Research Council (Vetenskapsrådet, 2014-02087, R.A.H. and K2015-61X-20776-08-3, M.J.), Swedish Childhood Cancer Foundation (Barncancerfonden, PR2014-0154 and NCP2015-0064, X.-M.Z.), Åke Wibergs stiftelse (M14-0263, X.-M.Z.), Foundation of Swedish MS Research (MS Forskningsfonden, L.K.), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, M.J.F. and D.F.J.K.), the Novo Nordisk Foundation (NNF15CC0018346, M.J.F. and D.F.J.K.), NIH-NINDS (1R01NS088137, O.B.), NIH-NIA (R01AG051812 and R01AG054672, O.B.), National Multiple Sclerosis Society (5092A1, O.B.) and Amyotrophic Lateral Sclerosis Association (ALSA2087, O.B.), and by a Nancy Davis Foundation Faculty Award (O.B.). X.-M.Z. was supported by a fellowship from the Swedish Childhood Cancer Foundation (Barncancerfonden, NC2014-0046, NBCNS). L.K. was supported by a fellowship from the Margaretha af Ugglas Foundation.
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Nature Reviews Neuroscience (2018)