Critical role of IRF-5 in the development of T helper 1 responses to Leishmania donovani infection.
The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5⁻/⁻ mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression.
Sidney Kimmel Comprehensive Center, The Johns Hopkins University, Baltimore, Maryland, United States of America.
Andrea
A
Paun
Rashmi
R
Bankoti
Trupti
T
Joshi
Paula M
PM
Pitha
Simona
S
Stäger
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006099:Granuloma / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D057809:HEK293 Cells / Q000201:enzymology; D006790:Host-Parasite Interactions; D006801:Humans; D007178:Inbreeding; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000502:physiology*; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D012333:RNA, Messenger; D008156:Luciferases; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
Immunol Rev. 2004 Oct;201:239-53
15361245
J Immunol. 1995 May 15;154(10):5320-30
7730635
Science. 2004 Mar 5;303(5663):1526-9
14976262
Immunity. 2009 Feb 20;30(2):242-53
19200759
J Biol Chem. 2001 Jun 29;276(26):23382-90
11303025
Eur J Immunol. 2003 Oct;33(10):2822-31
14515266
Immunobiology. 2008;213(3-4):377-87
18406382
Infect Immun. 2008 Jan;76(1):239-49
17998312
Immunity. 2006 Sep;25(3):417-28
16973389
Eur J Immunol. 1998 Feb;28(2):669-80
9521077
Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4664-8
20176957
Science. 2004 Mar 5;303(5663):1529-31
14976261
Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3855-60
18308927
Science. 2001 Feb 23;291(5508):1544-7
11222859
Nat Rev Immunol. 2006 Sep;6(9):644-58
16932750
Eur J Immunol. 2007 Dec;37(12):3424-34
18034422
Nat Immunol. 2001 Oct;2(10):907-16
11577346
J Immunol. 2008 May 1;180(9):5799-803
18424698
Nat Rev Immunol. 2003 Feb;3(2):133-46
12563297
Curr Opin Immunol. 2006 Feb;18(1):3-9
16343886
Infect Immun. 2004 Apr;72(4):1920-8
15039311
Eur J Immunol. 2006 Feb;36(2):411-20
16369915
J Biol Chem. 2005 Apr 29;280(17):17005-12
15695821
J Immunol. 2003 Nov 1;171(9):4561-8
14568929
J Exp Med. 2007 Apr 16;204(4):893-906
17389237
PLoS Pathog. 2010 Mar 12;6(3):e1000813
20300600
J Exp Med. 2007 May 14;204(5):1095-106
17438065
Nat Rev Immunol. 2003 Jan;3(1):23-35
12511873
Nature. 2005 Mar 10;434(7030):243-9
15665823
J Immunol. 2009 Feb 1;182(3):1386-96
19155485
Cell Mol Life Sci. 1999 Jul;55(8-9):1015-28
10484661
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3402-7
17360658
J Biol Chem. 2003 Jan 17;278(3):1910-4
12417590
Infect Immun. 1998 Jan;66(1):18-27
9423834
PLoS Pathog. 2009 Jul;5(7):e1000500
19578435
Eur J Immunol. 1998 Feb;28(2):687-95
9521079
J Immunol. 2009 May 15;182(10):6278-86
19414781
Cell. 2006 Feb 24;124(4):783-801
16497588
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5598-603
15034168
Nat Immunol. 2004 Oct;5(10):1061-8
15361868
J Biol Chem. 2004 Oct 22;279(43):45194-207
15308637
AIDS Res Hum Retroviruses. 2009 Dec;25(12):1287-95
19954299
J Immunol. 2003 Apr 15;170(8):4237-41
12682257
Nat Immunol. 2008 Dec;9(12):1399-406
18978793
J Biol Chem. 2008 May 23;283(21):14295-308
18332133
Cell Immunol. 2010;264(2):150-5
20579979
J Immunol. 2006 Sep 15;177(6):3515-9
16951309
J Immunol. 2000 Dec 15;165(12):7064-71
11120835
Science. 1999 Jul 30;285(5428):732-6
10426995