Defective inflammatory monocyte development in IRF8-deficient mice abrogates migration to the West Nile virus-infected brain.

Publisher: Karger Country of Publication: Switzerland NLM ID: 101469471 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1662-8128 (Electronic) Linking ISSN: 1662811X NLM ISO Abbreviation: J Innate Immun Subsets: MEDLINE

Original Publication: Basel, Switzerland : Karger, c2009-

Brain/*immunology ; Cell Movement/*immunology ; Interferon Regulatory Factors/*deficiency ; Monocytes/*immunology ; West Nile Fever/*immunology ; West Nile virus/*immunology; Animals ; Antigens, Ly/genetics ; Antigens, Ly/immunology ; Brain/pathology ; Brain/virology ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Cell Movement/genetics ; Inflammation/genetics ; Inflammation/microbiology ; Inflammation/pathology ; Integrin alpha4beta1/genetics ; Integrin alpha4beta1/immunology ; Macrophages/immunology ; Macrophages/pathology ; Mice ; Mice, Knockout ; Monocytes/pathology ; Receptors, CCR2/genetics ; Receptors, CCR2/immunology ; West Nile Fever/genetics ; West Nile Fever/pathology

IRF8 (interferon-regulatory factor-8) plays a critical role in regulating myeloid cell differentiation. However, the role of this transcription factor in the development of Ly6C+ inflammatory monocytes and their migration to the infected brain has not been examined. We have previously shown that West Nile virus (WNV) infection of wild-type (WT) mice triggers a significant increase in numbers of Ly6C+ monocytes in the bone marrow. These cells traffic via the blood to the infected brain, where they give rise to proinflammatory macrophages. Here, we show that WNV-infected IRF8-deficient (IRF8-/-) mice had significantly reduced numbers of Ly6C+ monocytes in the periphery, with few of these cells found in the blood. Furthermore, low numbers of inflammatory monocyte-derived macrophages were observed in the brains of IRF8-/- mice throughout infection. Adoptive transfer of IRF8-/- Ly6C+ monocytes demonstrated that these cells were intrinsically unable to traffic to the inflamed brain. Low expression of the chemokine receptor CCR2 and integrin VLA-4 by IRF8-/- monocytes likely contributed to this defect, as the interactions between these proteins and their ligands are critical for monocyte egress and migration to inflammatory foci. These data highlight a critical role for IRF8 in inflammatory monocyte differentiation and migration during WNV infection.
(© 2014 S. Karger AG, Basel.)

Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6898-903. (PMID: 9192663)
J Immunol. 2011 Feb 15;186(4):2382-96. (PMID: 21248254)
Eur J Immunol. 2011 Mar;41(3):634-44. (PMID: 21308682)
N Engl J Med. 2011 Jul 14;365(2):127-38. (PMID: 21524210)
Brain. 2009 Sep;132(Pt 9):2487-500. (PMID: 19531531)
Arch Virol. 1996;141(3-4):459-69. (PMID: 8645088)
J Immunol. 1998 Dec 15;161(12):6825-34. (PMID: 9862714)
Immunol Cell Biol. 2008 Jul;86(5):398-408. (PMID: 18392044)
Circulation. 2012 Jan 17;125(2):364-74. (PMID: 22144566)
J Immunol. 2003 Feb 1;170(3):1283-90. (PMID: 12538687)
Blood. 1999 Dec 1;94(11):3764-71. (PMID: 10572090)
Science. 2009 Jul 31;325(5940):612-6. (PMID: 19644120)
Annu Rev Immunol. 2009;27:669-92. (PMID: 19132917)
Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):2940-5. (PMID: 23382217)
Blood. 2012 Mar 1;119(9):2003-12. (PMID: 22238324)
Cell. 1996 Oct 18;87(2):307-17. (PMID: 8861914)
Nat Immunol. 2006 Mar;7(3):311-7. (PMID: 16462739)
J Exp Med. 2010 Apr 12;207(4):823-36. (PMID: 20351058)
Blood. 2012 Feb 9;119(6):1543-54. (PMID: 22117048)
Nat Immunol. 2011 Jul 03;12(8):778-85. (PMID: 21725321)
Blood. 2003 Feb 1;101(3):1155-63. (PMID: 12393599)
J Immunol. 2011 Jan 1;186(1):471-8. (PMID: 21131425)
Arterioscler Thromb Vasc Biol. 2011 Jul;31(7):1506-16. (PMID: 21677293)
J Neuroinflammation. 2010 Dec 15;7:92. (PMID: 21159187)
J Neurochem. 2007 Nov;103(3):1019-30. (PMID: 17854352)
Blood. 2013 Mar 7;121(10):1839-49. (PMID: 23319570)
J Exp Med. 2012 Jan 16;209(1):123-37. (PMID: 22213805)
Science. 2010 Feb 5;327(5966):656-61. (PMID: 20133564)
J Neuroinflammation. 2012 Oct 30;9:246. (PMID: 23111065)
Sci Transl Med. 2014 Jan 15;6(219):219ra7. (PMID: 24431111)
Blood. 2008 Nov 15;112(10):4028-38. (PMID: 18799728)
Blood. 2009 Apr 2;113(14):3190-7. (PMID: 19196868)
J Immunol. 2003 Feb 1;170(3):1131-5. (PMID: 12538667)
Nat Rev Immunol. 2004 Jun;4(6):432-44. (PMID: 15173832)
J Neurosci. 2011 Aug 3;31(31):11159-71. (PMID: 21813677)
J Exp Med. 2008 Sep 29;205(10):2319-37. (PMID: 18779347)
J Clin Invest. 2012 Sep;122(9):3063-87. (PMID: 22863620)

0 (Antigens, Ly)
0 (Ccr2 protein, mouse)
0 (Integrin alpha4beta1)
0 (Interferon Regulatory Factors)
0 (Ly-6C antigen, mouse)
0 (Receptors, CCR2)
0 (interferon regulatory factor-8)

Date Created: 20141004 Date Completed: 20150812 Latest Revision: 20211021

20250114

PMC6951104

10.1159/000365972

25277331