Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia

Journal of Experimental Medicine

Volumn 215, Issue 6, 2018, Pages 1627-1647

  Cronk, James C ^a,b   Filiano, Anthony J ^a,d   Louveau, Antoine ^a   Marin, Ioana ^a,b   Marsh, Rachel ^a   Ji, Emily ^a   Goldman, Dylan H ^a,b   Smirnov, Igor ^a   Geraci, Nicholas ^a   Acton, Scott ^c   Overall, Christopher C ^a   Kipnis, Jonathan ^a,b  

^a UNIVERSITY OF VIRGINIA   (United States)

^b UNIVERSITY OF VIRGINIA   (United States)

^c University of Virginia   (United States)

^d DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 ACYLGLYCEROPHOSPHOCHOLINE ACYLTRANSFERASE; ABHYDROLASE DOMAIN CONTAINING 6; ADAMTS1 PROTEIN; ADENOSINE A3 RECEPTOR; ADENOSINE TRIPHOSPHATASE; ADHESION G PROTEIN COUPLED RECEPTOR G1; BETA N ACETYLHEXOSAMINIDASE B; CALPAIN 3; CATHEPSIN L; CD34 ANTIGEN; CD81 ANTIGEN; CHEMOKINE RECEPTOR CX3CR1; COLONY STIMULATING FACTOR 1; CYSTATIN C; GLUCOSE TRANSPORTER 5; INTERLEUKIN 6; LACTATE DEHYDROGENASE; MEMBRANE PROTEIN; NOGO 66 RECEPTOR; PHOSPHORIBOSYL PYROPHOSPHATE SYNTHETASE ASSOCIATED PROTEIN 2; PROTEIN KINASE C ALPHA; PURINERGIC P2Y RECEPTOR; RHO GTPASE ACTIVATING PROTEIN 5; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; RIBOSEPHOSPHATE PYROPHOSPHOKINASE; SORTING NEXIN; SYNAPTOGYRIN; TRANSFORMING GROWTH FACTOR ALPHA; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BRAIN ENGRAFTING MACROPHAGE; BRAIN FUNCTION; BRAIN RADIATION; CELLS BY BODY ANATOMY; CENTRAL NERVOUS SYSTEM; CLINICAL ASSESSMENT; COMPARATIVE STUDY; CONTROLLED STUDY; ENGRAFTMENT; FEMALE; IMMUNE SYSTEM; LONG TERM CARE; MACROPHAGE; MALE; MICROGLIA; MOUSE; NONHUMAN; PHENOTYPIC VARIATION; PRIORITY JOURNAL; RNA SEQUENCE; WHOLE BODY RADIATION; ANIMAL; ANIMAL BEHAVIOR; BRAIN; C57BL MOUSE; DISEASE MODEL; GAMMA RADIATION; GENETIC TRANSCRIPTION; METABOLISM; PATHOLOGY; RADIATION RESPONSE; TRANSPLANTATION;

ANIMALS; BEHAVIOR, ANIMAL; BRAIN; DISEASE MODELS, ANIMAL; FEMALE; GAMMA RAYS; MACROPHAGES; MALE; MICE, INBRED C57BL; MICROGLIA; TRANSCRIPTION, GENETIC;

EID: 85048117956     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20180247     Document Type: Article

References (75)

1. Acton, S.T. 2001. Fast Algorithms for Area Morphology. Digit. Signal Process. 11:187-203. https:// doi .org/ 10 .1006/ dspr .2001 .0386
2. Acton, S.T., and D.P. Mukherjee. 2000. Area operators for edge detection. Pattern Recognit. Lett. 21:771-777. https:// doi .org/ 10 .1016/ S0167.-8655(00)00036-2
3. Acton, S.T., and N. Ray. 2006. Biomedical Image Analysis: Tracking. Morgan & Claypool Publishers. 152 pp
4. Ajami, B., J.L. Bennett, C. Krieger, W. Tetzlaff, and F.M. Rossi. 2007. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10:1538-1543. https:// doi .org/ 10. .1038/ nn2014
5. Alliot, F., I. Godin, and B. Pessac. 1999. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117:145-152. https:// doi .org/ 10 .1016/ S0165.-3806(99)00113-3
6. Anders, S., P.T. Pyl, and W. Huber. 2015. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics. 31:166-169. https:// doi .org/ 10 .1093/ bioinformatics/ btu638
7. Andrews, S. 2010. FastQC: a quality control tool for high throughput sequence data. Babraham Bioinformatics. Available at: http:// www .bioinformatics .babraham .ac .uk/ projects/ fastqc (accessed April 2016)
8. Ashburner, M., C.A. Ball, J.A. Blake, D. Botstein, H. Butler, J.M. Cherry, A.P. Davis, K. Dolinski, S.S. Dwight, J.T. Eppig, et al. The Gene Ontology Consortium. 2000. Gene ontology: tool for the unification of biology. Nat. Genet. 25:25-29. https:// doi .org/ 10 .1038/ 75556
9. Beattie, L., A. Sawtell, J. Mann, T.C.M. Frame, B. Teal, F. de Labastida Rivera, N. Brown, K. Walwyn-Brown, J.W.J. Moore, S. MacDonald, et al. 2016. Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions. J. Hepatol. 65:758-768. https:// doi .org/ 10 .1016/ j .jhep .2016 .05 .037
10. Bolger, A.M., M. Lohse, and B. Usadel. 2014. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 30:2114-2120. https:// doi .org/ 10 .1093/ bioinformatics/ btu170
11. Bosco, N., L.K. Swee, A. Benard, R. Ceredig, and A. Rolink. 2010. Auto-reconstitution of the T-cell compartment by radioresistant hematopoietic cells following lethal irradiation and bone marrow transplantation. Exp. Hematol. 38:222-232
12. Bruttger, J., K. Karram, S. Wörtge, T. Regen, F. Marini, N. Hoppmann, M. Klein, T. Blank, S. Yona, Y. Wolf, et al. 2015. Genetic Cell Ablation Reveals Clusters of Local Self-Renewing Microglia in the Mammalian Central Nervous System. Immunity. 43:92-106. https:// doi .org/ 10 .1016/ j .immuni .2015 .06 .012
13. Butovsky, O., M. Koronyo-Hamaoui, G. Kunis, E. Ophir, G. Landa, H. Cohen, and M. Schwartz. 2006. Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc. Natl. Acad. Sci. USA. 103:11784-11789. https:// doi .org/ 10 .1073/ pnas .0604681103
14. Butovsky, O., G. Kunis, M. Koronyo-Hamaoui, and M. Schwartz. 2007. Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer's disease model. Eur. J. Neurosci. 26:413-416. https:// doi .org/ 10 .1111/ j .1460-9568 .2007 .05652 .x
15. Butovsky, O., S. Siddiqui, G. Gabriely, A.J. Lanser, B. Dake, G. Murugaiyan, C.E. Doykan, P.M. Wu, R.R. Gali, L.K. Iyer, et al. 2012. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J. Clin. Invest. 122:3063-3087. https:// doi .org/ 10 .1172/ JCI62636
16. Carvalho, B.S., and R.A. Irizarry. 2010. A framework for oligonucleotide microarray preprocessing. Bioinformatics. 26:2363-2367. https:// doi .org/ 10 .1093/ bioinformatics/ btq431
17. Chen, S.K., P. Tvrdik, E. Peden, S. Cho, S. Wu, G. Spangrude, and M.R. Capecchi. 2010. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell. 141:775-785. https:// doi .org/ 10 .1016/ j .cell .2010 .03 .055
18. Chiu, I.M., E.T. Morimoto, H. Goodarzi, J.T. Liao, S. O'Keeffe, H.P. Phatnani, M. Muratet, M.C. Carroll, S. Levy, S. Tavazoie, et al. 2013. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Reports. 4:385-401. https:// doi .org/ 10 .1016/ j .celrep .2013 .06 .018
19. Cronk, J.C., N.C. Derecki, E. Ji, Y. Xu, A.E. Lampano, I. Smirnov, W. Baker, G.T. Norris, I. Marin, N. Coddington, et al. 2015. Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli. Immunity. 42:679-691. https:// doi .org/ 10 .1016/ j .immuni .2015 .03 .013
20. Davalos, D., J. Grutzendler, G. Yang, J.V. Kim, Y. Zuo, S. Jung, D.R. Littman, M.L. Dustin, and W.B. Gan. 2005. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8:752-758. https:// doi .org/ 10. .1038/ nn1472
21. Derecki, N.C., J.C. Cronk, Z. Lu, E. Xu, S.B. Abbott, P.G. Guyenet, and J. Kipnis. 2012. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature. 484:105-109. https:// doi .org/ 10 .1038/ nature10907
22. Dobin, A., C.A. Davis, F. Schlesinger, J. Drenkow, C. Zaleski, S. Jha, P. Batut, M. Chaisson, and T.R. Gingeras. 2013. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 29:15-21. https:// doi .org/ 10 .1093/ bioinformatics/ bts635
23. Elmore, M.R., A.R. Najafi, M.A. Koike, N.N. Dagher, E.E. Spangenberg, R.A. Rice, M. Kitazawa, B. Matusow, H. Nguyen, B.L. West, and K.N. Green. 2014. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 82:380-397. https:// doi .org/ 10 .1016/ j .neuron .2014 .02. .040
24. Epelman, S., K.J. Lavine, A.E. Beaudin, D.K. Sojka, J.A. Carrero, B. Calderon, T. Brija, E.L. Gautier, S. Ivanov, A.T. Satpathy, et al. 2014. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity. 40:91-104. https:// doi .org/ 10 .1016/ j .immuni .2013 .11 .019
25. Filiano, A.J., Y. Xu, N.J. Tustison, R.L. Marsh, W. Baker, I. Smirnov, C.C. Overall, S.P. Gadani, S.D. Turner, Z. Weng, et al. 2016. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 535:425-429. https:// doi .org/ 10 .1038/ nature18626
26. Gautier, L., L. Cope, B.M. Bolstad, and R.A. Irizarry. 2004. affy-analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 20:307-315. https:// doi .org/ 10 .1093/ bioinformatics/ btg405
27. Gehlenborg, N. 2016. UpSetR: A More Scalable Alternative to Venn and Euler Diagrams for Visualizing Intersecting Sets. R package version 1.2.2. Available at: https:// rdrr .io/ cran/ UpSetR/ (accessed April 2016)
28. Gibbings, S.L., R. Goyal, A.N. Desch, S.M. Leach, M. Prabagar, S.M. Atif, D.L. Bratton, W. Janssen, and C.V. Jakubzick. 2015. Transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages. Blood. 126:1357-1366. https:// doi .org/ 10 .1182/ blood-2015-01-624809
29. Ginhoux, F., and M. Merad. 2011. [Microglia arise from extra-embryonic yolk sac primitive progenitors]. Med. Sci. (Paris). 27:719-724. https:// doi .org/ 10 .1051/ medsci/ 2011278013
30. Goldmann, T., P. Wieghofer, P.F. Müller, Y. Wolf, D. Varol, S. Yona, S.M. Brendecke, K. Kierdorf, O. Staszewski, M. Datta, et al. 2013. A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat. Neurosci. 16:1618-1626. https:// doi .org/ 10 .1038/ nn .3531
31. Hänzelmann, S., R. Castelo, and J. Guinney. 2013. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 14:7. https:// doi .org/ 10 .1186/ 1471-2105-14-7
32. Harrow, J., A. Frankish, J.M. Gonzalez, E. Tapanari, M. Diekhans, F. Kokocinski, B.L. Aken, D. Barrell, A. Zadissa, S. Searle, et al. 2012. GEN CODE: the reference human genome annotation for The ENC ODE Project. Genome Res. 22:1760-1774. https:// doi .org/ 10 .1101/ gr .135350 .111
33. Heng, T.S., and M.W. Painter. Immunological Genome Project Consortium. 2008. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9:1091-1094. https:// doi .org/ 10. .1038/ ni1008-1091
34. Hoeffel, G., J. Chen, Y. Lavin, D. Low, F.F. Almeida, P. See, A.E. Beaudin, J. Lum, I. Low, E.C. Forsberg, et al. 2015. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity. 42:665-678. https:// doi .org/ 10 .1016/ j .immuni .2015. .03 .011
35. Hsiao, E.Y., S.W. McBride, J. Chow, S.K. Mazmanian, and P.H. Patterson. 2012. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc. Natl. Acad. Sci. USA. 109:12776-12781. https:// doi .org/ 10. .1073/ pnas .1202556109
36. Huang, Y., Z. Xu, S. Xiong, F. Sun, G. Qin, G. Hu, J. Wang, L. Zhao, Y.X. Liang, T. Wu, et al. 2018. Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat. Neurosci. https:// doi .org/ 10 .1038/ s41593-018-0090-8
37. Irizarry, R.A., B.M. Bolstad, F. Collin, L.M. Cope, B. Hobbs, and T.P. Speed. 2003. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31:e15. https:// doi .org/ 10 .1093/ nar/ gng015
38. Jay, T.R., C.M. Miller, P.J. Cheng, L.C. Graham, S. Bemiller, M.L. Broihier, G. Xu, D. Margevicius, J.C. Karlo, G.L. Sousa, et al. 2015. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J. Exp. Med. 212:287-295. https:// doi .org/ 10 .1084/ jem .20142322
39. Jung, S., and M. Schwartz. 2012. Non-identical twins-microglia and monocyte-derived macrophages in acute injury and autoimmune inflammation. Front. Immunol. 3:89. https:// doi .org/ 10 .3389/ fimmu .2012 .00089
40. Kolde, R. 2015. Pretty Heatmaps. R package version 1.0.8. Available at: https:// github .com/ raivokolde/ pheatmap (accessed April 2016)
41. Krivit, W., J.H. Sung, E.G. Shapiro, and L.A. Lockman. 1995. Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases. Cell Transplant. 4:385-392. https:// doi .org/ 10 .1177/ 096368979500400409
42. Krivit, W., C. Peters, and E.G. Shapiro. 1999. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr. Opin. Neurol. 12:167-176. https:// doi .org/ 10 .1097/ 00019052-199904000.-00007
43. Larochelle, A., M.A. Bellavance, J.P. Michaud, and S. Rivest. 2016. Bone marrow-derived macrophages and the CNS: An update on the use of experimental chimeric mouse models and bone marrow transplantation in neurological disorders. Biochim. Biophys. Acta. 1862:310-322. https:// doi .org/ 10 .1016/ j .bbadis .2015 .09 .017
44. Lassmann, T., Y. Hayashizaki, and C.O. Daub. 2011. SAMStat: monitoring biases in next generation sequencing data. Bioinformatics. 27:130-131. https:// doi .org/ 10 .1093/ bioinformatics/ btq614
45. Lavin, Y., D. Winter, R. Blecher-Gonen, E. David, H. Keren-Shaul, M. Merad, S. Jung, and I. Amit. 2014. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 159:1312-1326. https:// doi .org/ 10 .1016/ j .cell .2014 .11 .018
46. Law, C.W., Y. Chen, W. Shi, and G.K. Smyth. 2014. voom: Precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 15:R29. https:// doi .org/ 10 .1186/ gb-2014-15-2-r29
47. Leek, J.T., and J.D. Storey. 2007. Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet. 3:1724-1735. https:// doi .org/ 10 .1371/ journal .pgen .0030161
48. Leek, J.T., W.E. Johnson, H.S. Parker, A.E. Jaffe, and J.D. Storey. 2012. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 28:882-883. https:// doi .org/ 10 .1093/ bioinformatics/ bts034
49. Lex, A., N. Gehlenborg, H. Strobelt, R. Vuillemot, and H. Pfister. 2014. UpSet: Visualization of Intersecting Sets. IEEE Trans. Vis. Comput. Graph. 20:1983-1992. https:// doi .org/ 10 .1109/ TVCG .2014 .2346248
50. Li, H., B. Handsaker, A. Wysoker, T. Fennell, J. Ruan, N. Homer, G. Marth, G. Abecasis, and R. Durbin. 1000 Genome Project Data Processing Subgroup. 2009. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 25:2078-2079. https:// doi .org/ 10 .1093/ bioinformatics/ btp352
51. Li, J., K. Chen, L. Zhu, and J.W. Pollard. 2006. Conditional deletion of the colony stimulating factor-1 receptor (c-fms proto-oncogene) in mice. Genesis. 44:328-335. https:// doi .org/ 10 .1002/ dvg .20219
52. Love, M.I., W. Huber, and S. Anders. 2014. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15:550. https:// doi .org/ 10 .1186/ s13059-014-0550-8
53. Lu, Z., M.R. Elliott, Y. Chen, J.T. Walsh, A.L. Klibanov, K.S. Ravichandran, and J. Kipnis. 2011. Phagocytic activity of neuronal progenitors regulates adult neurogenesis. Nat. Cell Biol. 13:1076-1083. https:// doi .org/ 10 .1038/ ncb2299
54. Matcovitch-Natan, O., D.R. Winter, A. Giladi, S. Vargas Aguilar, A. Spinrad, S. Sarrazin, H. Ben-Yehuda, E. David, F. Zelada González, P. Perrin, et al. 2016. Microglia development follows a stepwise program to regulate brain homeostasis. Science. 353:aad8670. https:// doi .org/ 10 .1126/ science .aad8670
55. Mildner, A., H. Schmidt, M. Nitsche, D. Merkler, U.K. Hanisch, M. Mack, M. Heikenwalder, W. Brück, J. Priller, and M. Prinz. 2007. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat. Neurosci. 10:1544-1553. https:// doi .org/ 10 .1038/ nn2015
56. Platt, F.M., and R.H. Lachmann. 2009. Treating lysosomal storage disorders: current practice and future prospects. Biochim. Biophys. Acta. 1793:737-745. https:// doi .org/ 10 .1016/ j .bbamcr .2008 .08 .009
57. Priller, J., A. Flügel, T. Wehner, M. Boentert, C.A. Haas, M. Prinz, F. Fernández-Klett, K. Prass, I. Bechmann, B.A. de Boer, et al. 2001. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat. Med. 7:1356-1361. https:// doi .org/ 10 .1038/ nm1201-1356
58. Prinz, M., and J. Priller. 2014. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15:300-312. https:// doi .org/ 10 .1038/ nrn3722
59. Radjavi, A., I. Smirnov, N. Derecki, and J. Kipnis. 2014. Dynamics of the meningeal CD4(+) T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice. Mol. Psychiatry. 19:531-533. https:// doi .org/ 10 .1038/ mp .2013 .79
60. Ritchie, M.E., B. Phipson, D. Wu, Y. Hu, C.W. Law, W. Shi, and G.K. Smyth. 2015. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43:e47. https:// doi .org/ 10. .1093/ nar/ gkv007
61. Rolls, A., R. Shechter, A. London, Y. Segev, J. Jacob-Hirsch, N. Amariglio, G. Rechavi, and M. Schwartz. 2008. Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Med. 5:e171. https:// doi .org/ 10 .1371/ journal .pmed .0050171
62. Scott, C.L., F. Zheng, P. De Baetselier, L. Martens, Y. Saeys, S. De Prijck, S. Lippens, C. Abels, S. Schoonooghe, G. Raes, et al. 2016. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7:10321. https:// doi .org/ 10 .1038/ ncomms10321
63. Shechter, R., A. London, C. Varol, C. Raposo, M. Cusimano, G. Yovel, A. Rolls, M. Mack, S. Pluchino, G. Martino, et al. 2009. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6:e1000113. https:// doi .org/ 10 .1371/ journal .pmed .1000113
64. Sheng, J., C. Ruedl, and K. Karjalainen. 2015. Most Tissue-Resident Macrophages Except Microglia Are Derived from Fetal Hematopoietic Stem Cells. Immunity. 43:382-393. https:// doi .org/ 10 .1016/ j .immuni .2015 .07. .016
65. Silver, J.D., M.E. Ritchie, and G.K. Smyth. 2009. Microarray background correction: maximum likelihood estimation for the normal-exponential convolution. Biostatistics. 10:352-363. https:// doi .org/ 10 .1093/ biostatistics/ kxn042
66. Srinivasan, K., B.A. Friedman, J.L. Larson, B.E. Lauffer, L.D. Goldstein, L.L. Appling, J. Borneo, C. Poon, T. Ho, F. Cai, et al. 2016. Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses. Nat. Commun. 7:11295. https:// doi .org/ 10 .1038/ ncomms11295
67. Takata, K., T. Kozaki, C.Z.W. Lee, M.S. Thion, M. Otsuka, S. Lim, K.H. Utami, K. Fidan, D.S. Park, B. Malleret, et al. 2017. Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function. Immunity. 47:183-198
68. The Gene Ontology Consortium. 2017. Expansion of the Gene Ontology knowledgebase and resources. Nucleic Acids Res. 45(D1):D331-D338. https:// doi .org/ 10 .1093/ nar/ gkw1108
69. Thériault, P., A. ElAli, and S. Rivest. 2015. The dynamics of monocytes and microglia in Alzheimer's disease. Alzheimers Res. Ther. 7:41. https:// doi .org/ 10 .1186/ s13195-015-0125-2
70. van de Laar, L., W. Saelens, S. De Prijck, L. Martens, C.L. Scott, G. Van Isterdael, E. Hoffmann, R. Beyaert, Y. Saeys, B.N. Lambrecht, and M. Guilliams. 2016. Yolk Sac Macrophages, Fetal Liver, and Adult Monocytes Can Colonize an Empty Niche and Develop into Functional Tissue-Resident Macrophages. Immunity. 44:755-768. https:// doi .org/ 10 .1016/ j .immuni .2016 .02 .017
71. Walkley, S.U., M.A. Thrall, K. Dobrenis, M. Huang, P.A. March, D.A. Siegel, and S. Wurzelmann. 1994. Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease. Proc. Natl. Acad. Sci. USA. 91:2970-2974. https:// doi .org/ 10 .1073/ pnas .91 .8 .2970
72. Wang, Y., T.K. Ulland, J.D. Ulrich, W. Song, J.A. Tzaferis, J.T. Hole, P. Yuan, T.E. Mahan, Y. Shi, S. Gilfillan, et al. 2016. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213:667-675. https:// doi .org/ 10 .1084/ jem .20151948
73. Wu, D., and G.K. Smyth. 2012. Camera: a competitive gene set test accounting for inter-gene correlation. Nucleic Acids Res. 40:e133. https:// doi .org/ 10. .1093/ nar/ gks461
74. Yamasaki, R., H. Lu, O. Butovsky, N. Ohno, A.M. Rietsch, R. Cialic, P.M. Wu, C.E. Doykan, J. Lin, A.C. Cotleur, et al. 2014. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211:1533-1549. https:// doi .org/ 10 .1084/ jem .20132477
75. Yona, S., K.W. Kim, Y. Wolf, A. Mildner, D. Varol, M. Breker, D. Strauss-Ayali, S. Viukov, M. Guilliams, A. Misharin, et al. 2013. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 38:79-91. https:// doi .org/ 10 .1016/ j .immuni .2012 .12 .001