title: RON receptor tyrosine kinase, a negative regulator of inflammation, is decreased during simian immunodeficiency virus-associated central nervous system disease.
abstract: Expressed on tissue-resident macrophages, the receptor tyrosine kinase, recepteur d'orgine nantais (RON), functions to maintain inflammation homeostasis by activating genes that promote wound repair and resolve inflammation while repressing genes that perpetuate tissue damage and cell death. Chronic HIV-1 infection is associated with dysregulated inflammation, and we hypothesize that diminished RON expression contributes to the development of end organ diseases such as HIV-1-associated CNS disease. To explore RON function in vivo, we used CNS tissue from a well-characterized SIV macaque model and examined the temporal regulation of RON in the brain during the course of infection. Following prolonged SIV infection, RON expression was inversely correlated with the development of CNS disease; RON was maintained in animals that did not develop CNS lesions and was reduced in SIV-infected macaques that demonstrated moderate to severe inflammatory lesions. Arginase-1 expression was reduced in the brain during late infection, whereas expression of the inflammatory genes, IL-12p40 and TNF-α, was elevated. To validate a role for RON in regulating HIV-1 in primary cells, we used human tissue-resident macrophages isolated from tonsil as a tractable cell model. RON signaling in tissue-resident macrophages, both ligand dependent and independent, limited HIV-1 replication. Furthermore, prolonged HIV-1 infection in vitro resulted in downregulation of RON. We propose a model in which, following chronic HIV-1 infection in the brain, RON expression is decreased, genes that quell inflammation are repressed, and inflammatory mediators are induced to promote tissue inflammation.
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Daniele C
authors.initials: DC
authors.lastname: Cary
authors.forename: Janice E
authors.initials: JE
authors.lastname: Clements
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Henderson
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002493:Central Nervous System Diseases / Q000276:immunology* / Q000821:virology; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007249:Inflammation; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D008254:Macaca nemestrina; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D053762:Interleukin-12 Subunit p40; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C544448:Arg1 protein, mouse; D001119:Arginase
references.citation: J Infect Dis. 2006 Apr 1;193(7):963-70
references.pmid: 16518758
references.citation: AIDS. 2009 Aug 24;23(13):1743-53
references.pmid: 19571723
references.citation: Nat Rev Immunol. 2010 May;10(5):365-76
references.pmid: 20414208
references.citation: Ann Surg. 2001 Mar;233(3):393-9
references.pmid: 11224628
references.citation: Am J Med. 1994 Sep;97(3):289-95
references.pmid: 8092178
references.citation: J Neurovirol. 2008 Aug;14(4):309-17
references.pmid: 18780232
references.citation: Crit Care Med. 2008 May;36(5):1585-93
references.pmid: 18434891
references.citation: BMC Infect Dis. 2012 Oct 29;12:274
references.pmid: 23106848
references.citation: J Immunol. 2007 Dec 1;179(11):7916-23
references.pmid: 18025239
references.citation: AIDS. 2006 Jan 9;20(2):197-205
references.pmid: 16511412
references.citation: Am J Respir Cell Mol Biol. 2002 Jan;26(1):99-104
references.pmid: 11751209
references.citation: J Immunol. 2008 Jul 15;181(2):1548-55
references.pmid: 18606710
references.citation: J Leukoc Biol. 2003 Nov;74(5):635-41
references.pmid: 12960232
references.citation: J Immunol. 2005 Jan 15;174(2):834-45
references.pmid: 15634905
references.citation: Scand J Immunol. 2002 Dec;56(6):545-53
references.pmid: 12472665
references.citation: Nat Med. 1995 Dec;1(12):1320-2
references.pmid: 7489416
references.citation: Nat Rev Immunol. 2005 Jan;5(1):69-81
references.pmid: 15630430
references.citation: Nature. 1993 Mar 25;362(6418):355-8
references.pmid: 8455722
references.citation: J Virol. 2003 Apr;77(7):4081-94
references.pmid: 12634367
references.citation: J Immunol. 1999 Dec 15;163(12):6606-13
references.pmid: 10586055
references.citation: J Trauma. 2001 Sep;51(3):497-502
references.pmid: 11535898
references.citation: J Immunol. 2002 Mar 15;168(6):2895-903
references.pmid: 11884460
references.citation: J Immunol. 2000 Apr 1;164(7):3815-21
references.pmid: 10725742
references.citation: Science. 1997 May 9;276(5314):960-4
references.pmid: 9139661
references.citation: J Biol Chem. 2010 Jan 22;285(4):2258-73
references.pmid: 19933495
references.citation: J Immunol. 2008 Feb 1;180(3):1670-7
references.pmid: 18209063
references.citation: J Neurovirol. 2011 Feb;17(1):120-30
references.pmid: 21165785
references.citation: Nat Rev Immunol. 2008 Jan;8(1):34-47
references.pmid: 18064051
references.citation: J Immunol. 2011 Sep 1;187(5):2181-92
references.pmid: 21810604
references.citation: AIDS. 2012 Jun 19;26(10):1231-41
references.pmid: 22706009
references.citation: Am J Pathol. 2011 Oct;179(4):1623-9
references.pmid: 21871429
references.citation: Infect Immun. 2002 Jan;70(1):416-8
references.pmid: 11748211
references.citation: J Immunol. 2012 Apr 15;188(8):3876-85
references.pmid: 22407919
references.citation: J Leukoc Biol. 2004 May;75(5):731-7
references.pmid: 14726496
references.citation: J Immunol. 2010 Dec 15;185(12):7309-16
references.pmid: 21078906
references.citation: J Immunol. 2008 Aug 15;181(4):2303-10
references.pmid: 18684919
references.citation: Genes Funct. 1997 Feb;1(1):69-83
references.pmid: 9680329
references.citation: J Virol. 2005 Apr;79(8):5220-6
references.pmid: 15795306
references.citation: Hepatology. 2011 May;53(5):1618-28
references.pmid: 21520175
references.citation: J Virol. 1999 Dec;73(12):10480-8
references.pmid: 10559366
references.citation: Cytometry. 2002 Jul 1;48(3):167-76
references.pmid: 12116363
references.citation: Nat Rev Neurosci. 2007 Jan;8(1):57-69
references.pmid: 17180163
references.citation: J Neuroimmune Pharmacol. 2009 Dec;4(4):430-47
references.pmid: 19768553
references.citation: J Biol Chem. 2005 Oct 21;280(42):35098-107
references.pmid: 16103119
references.citation: J Immunol. 2006 Nov 15;177(10):7303-11
references.pmid: 17082649
references.citation: J Virol. 2011 Oct;85(20):10834-50
references.pmid: 21849441
references.citation: J Immunol. 2004 Dec 1;173(11):6864-72
references.pmid: 15557181
references.citation: Curr Opin HIV AIDS. 2011 Jan;6(1):37-42
references.pmid: 21242892
references.citation: Am J Physiol. 1998 Jan;274(1):H342-8
references.pmid: 9458885
references.citation: J Immunol. 2002 Jan 15;168(2):853-60
references.pmid: 11777982
references.citation: FEMS Immunol Med Microbiol. 2012 Nov;66(2):265-8
references.pmid: 22827286
references.citation: Am J Pathol. 1976 May;83(2):341-58
references.pmid: 1083675
references.citation: J Immunol. 2001 Jun 1;166(11):6861-8
references.pmid: 11359846
references.citation: J Invest Dermatol. 1998 Oct;111(4):573-81
references.pmid: 9764835
references.citation: J Immunol. 2007 Dec 1;179(11):7262-9
references.pmid: 18025168
references.citation: Nat Immunol. 2011 Jul 03;12(8):742-51
references.pmid: 21725320
references.citation: J Immunol. 2004 Feb 1;172(3):1825-32
references.pmid: 14734766
references.citation: Neurology. 1992 Sep;42(9):1736-9
references.pmid: 1513462
references.citation: J Virol. 2009 Sep;83(18):9247-57
references.pmid: 19570871
references.citation: Ann Neurol. 2005 Jun;57(6):883-95
references.pmid: 15929040
references.citation: Shock. 2010 Feb;33(2):197-204
references.pmid: 19487969
references.citation: PLoS One. 2009 Dec 17;4(12):e8129
references.pmid: 20019816
references.citation: Blood. 2002 Jan 1;99(1):111-20
references.pmid: 11756160
references.citation: Acta Otolaryngol Suppl. 1988;454:108-12
references.pmid: 3223242