Ly6c+ "inflammatory monocytes" are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis.
In a lethal West Nile virus (WNV) model, central nervous system infection triggered a threefold increase in CD45(int)/CD11b(+)/CD11c(-) microglia at days 6-7 postinfection (p.i.). Few microglia were proliferating, suggesting that the increased numbers were derived from a migratory precursor cell. Depletion of "circulating" (Gr1(-)(Ly6C(lo))CX3CR1(+)) and "inflammatory" (Gr1(hi)/Ly6C(hi)/CCR2(+)) classical monocytes during infection abrogated the increase in microglia. C57BL/6 chimeras reconstituted with cFMS-enhanced green fluorescent protein (EGFP) bone marrow (BM) showed large numbers of peripherally derived (GFP(+)) microglia expressing GR1(+)(Ly6C(+)) at day 7 p.i., suggesting that the inflammatory monocyte is a microglial precursor. This was confirmed by adoptive transfer of labeled BM (Ly6C(hi)/CD115(+)) or circulating inflammatory monocytes that trafficked to the WNV-infected brain and expressed a microglial phenotype. CCL2 is a chemokine that is highly expressed during WNV infection and important in inflammatory monocyte trafficking. Neutralization of CCL2 not only reduced the number of GFP(+) microglia in the brain during WNV infection but prolonged the life of infected animals. Therefore, CCL2-dependent inflammatory monocyte migration is critical for increases in microglia during WNV infection and may also play a pathogenic role during WNV encephalitis.
Getts
Daniel R
DR
The Discipline of Pathology, School of Medical Sciences, The University of Sydney, Sydney NSW 2006, Australia.
Terry
Rachael L
RL
Getts
Meghann Teague
MT
Müller
Marcus
M
Rana
Sabita
S
Shrestha
Bimmi
B
Radford
Jane
J
Van Rooijen
Nico
N
Campbell
Iain L
IL
King
Nicholas J C
NJ
D019264:Adoptive Transfer; D000818:Animals; D000950:Antigens, Ly / Q000276:immunology*; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D018932:Chemokine CCL2 / Q000276:immunology; D004002:Clodronic Acid / Q000378:metabolism; D005260:Female; D017493:Leukocyte Common Antigens / Q000276:immunology; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology*; D015996:Survival Rate; D014901:West Nile Fever / Q000276:immunology* / Q000473:pathology; D014902:West Nile virus
D000950:Antigens, Ly; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008081:Liposomes; C494192:Ly-6C antigen, mouse; D004002:Clodronic Acid; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse
Nat Immunol. 2006 Mar;7(3):311-7
16462739
J Neuroimmunol. 1996 May;66(1-2):103-14
8964903
J Neuroimmunol. 1993 Nov-Dec;48(2):189-98
8227316
J Neuropathol Exp Neurol. 2006 May;65(5):499-507
16772873
J Immunol. 2003 Sep 1;171(5):2524-31
12928402
Curr Opin Immunol. 2006 Feb;18(1):49-53
16338128
J Immunol. 2007 Feb 15;178(4):2000-7
17277103
Glia. 1988;1(5):301-7
2976393
Methods Enzymol. 2003;373:3-16
14714393
Biochem Biophys Res Commun. 1998 Apr 28;245(3):734-40
9588184
J Immunol. 2006 Nov 15;177(10):6871-9
17082601
J Neurochem. 2005 Nov;95(4):1069-77
16135085
Glia. 2006 May;53(7):744-53
16518833
Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):860-6
17011458
Nat Neurosci. 2007 Dec;10(12):1544-53
18026096
Nat Med. 2004 Dec;10(12):1366-73
15558055
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17140-5
17939996
Bull Acad Natl Med. 2001;185(2):337-46; discussion 346-7
11474589
Eur J Immunol. 1992 Jan;22(1):175-82
1346110
Blood. 2003 Feb 1;101(3):1155-63
12393599
Brain. 1991 Feb;114 ( Pt 1B):557-72
2004256
Glia. 1996 Jan;16(1):51-64
8787773
Nature. 2005 Jun 16;435(7044):969-73
15959517
Brain Res Dev Brain Res. 1999 Jun 8;115(1):71-81
10366704
J Neurochem. 2007 Nov;103(3):1019-30
17854352
J Clin Invest. 2007 Apr;117(4):902-9
17364026
J Immunol. 2007 Jan 1;178(1):39-48
17182538
Immunobiology. 2006;211(6-8):609-18
16920499
J Exp Med. 2006 Mar 20;203(3):583-97
16492803
Immunity. 2003 Jul;19(1):71-82
12871640
Arzneimittelforschung. 1995 Mar;45(3A):357-60
7763326
J Comp Neurol. 2003 Mar 31;458(2):144-57
12596255
Neuroscience. 1990;39(1):151-70
2089275
Eur J Neurosci. 2007 Mar;25(6):1711-24
17432960
Stem Cells. 2007 Dec;25(12):3165-72
17761757
J Immunol. 2004 Apr 1;172(7):4410-7
15034056
J Virol. 1997 Dec;71(12):9323-32
9371591
Brain Pathol. 2000 Apr;10(2):260-72
10764045
J Exp Med. 1998 Aug 3;188(3):465-74
9687524
Am J Pathol. 2003 Feb;162(2):427-38
12547701
Lab Invest. 1991 Mar;64(3):345-51
2002653
J Neuroimmunol. 2001 Jun 1;116(2):188-95
11438173
Trends Biotechnol. 1997 May;15(5):178-85
9161052
Keio J Med. 1996 Sep;45(3):239-47
8897767
Nat Neurosci. 2006 Jul;9(7):917-24
16732273
Glia. 1998 Jan;22(1):72-85
9436789
J Clin Invest. 2007 Oct;117(10):3059-66
17909632
Arch Virol. 1996;141(3-4):459-69
8645088
FASEB J. 2004 Jun;18(9):998-1000
15084516
Neurosci Lett. 2005 Sep 16;385(3):220-3
15964677
J Gen Virol. 2008 Feb;89(Pt 2):467-473
18198377
J Immunol. 2007 Sep 1;179(5):2774-86
17709491
Int J Biochem Cell Biol. 2005 Jan;37(1):17-21
15381143
Glia. 1995 Dec;15(4):437-46
8926037
Neuron. 2006 Feb 16;49(4):489-502
16476660
Am J Pathol. 1999 Dec;155(6):1915-27
10595922
J Exp Med. 2006 Jan 23;203(1):35-40
16418398
J Immunol Methods. 1994 Sep 14;174(1-2):83-93
8083541
J Virol. 1994 Oct;68(10):6291-8
7916058
Nat Immunol. 2006 Mar;7(3):265-73
16444257
J Clin Invest. 2007 Jan;117(1):185-94
17200718
Immunol Cell Biol. 2007 Jan;85(1):33-42
17146465
Brain. 2006 Sep;129(Pt 9):2394-403
16891321
Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7438-42
1651506
J Neurosci Res. 1991 Dec;30(4):593-600
1724016
J Virol. 2003 Feb;77(4):2578-86
12551996
J Virol. 2007 Jan;81(2):860-71
17079283
Neuropathol Appl Neurobiol. 2000 Oct;26(5):454-62
11054186
Hum Pathol. 2000 May;31(5):527-31
10836291