title: The IL-33/ST2 axis is associated with human visceral leishmaniasis and suppresses Th1 responses in the livers of BALB/c mice infected with Leishmania donovani.
abstract: During visceral leishmaniasis, the control of hepatic parasite burden is mainly due to granuloma assembly in a microenvironment consisting of both Th1 and Th2 components. Using enzyme-linked immunosorbent assay (ELISA) dosages, quantitative PCR (qPCR), immunohistochemistry, and flow cytometry, we studied the role of interleukin-33 (IL-33), a recently described cytokine signaling through the ST2 receptor, during visceral leishmaniasis. We showed that a higher level of IL-33 was detected in the serum of patients with visceral leishmaniasis than in that from healthy donors and demonstrated the presence of IL-33(+) cells in a liver biopsy specimen from a patient. Similarly, in BALB/c mice experimentally infected with L. donovani, a higher level of IL-33 was detected in the serum, as well as the presence of IL-33(+) cells and ST2(+) cells in the mouse liver. In ST2(-/-) BALB/c mice, better control of the hepatic parasite burden and reduced hepatomegaly were observed. This was associated with strong induction of Th1 cytokines (gamma interferon [IFN-γ] and IL-12) compared to the level in wild-type (WT) mice and better recruitment of myeloid cells associated with strongly induced chemokines (CCL2 and CXCL2) and receptors (CCR2 and CXCR2). Conversely, BALB/c mice treated twice weekly with recombinant IL-33 showed a dramatically reduced induction of Th1 cytokines and delayed inhibition of monocyte and neutrophil recruitment in the liver, which was associated with reduced KC/CXCL1 and CXCR2 expression. Taken together, our results suggest that IL-33 could be a new deleterious regulator of the hepatic immune response against Leishmania donovani, via the repression of the Th1 response and myeloid cell recruitment.
  
  
  OBJECTIVE
  Visceral leishmaniasis is a life-threatening systemic disease due to the Leishmania protozoa L. infantum and L. donovani and is ranked by the World Health Organization as the second most important protozoan parasitic disease after malaria for its grave morbidity, high mortality, and global distribution. Leishmania parasites subvert the host's immune response to propagate to target organs, including the spleen, the bone marrow, and the liver. Control of hepatic parasite burdens depends on a delicate and poorly understood Th1/Th2 immune balance. To better understand this complex immune response, new cytokines are interesting targets for research studies. IL-33 is a newly described cytokine usually associated with Th2 response and involved in different diseases, including infectious diseases and hepatitis. Our results suggest that IL-33 could be a new factor of susceptibility and a potential prognostic marker during visceral leishmaniasis.
authors.affiliation: Inserm U1085, IRSET, Rennes, France.
authors.forename: Octavie
authors.initials: O
authors.lastname: Rostan
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gangneux
authors.forename: Claire
authors.initials: C
authors.lastname: Piquet-Pellorce
authors.forename: Christelle
authors.initials: C
authors.lastname: Manuel
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.forename: Claude
authors.initials: C
authors.lastname: Guiguen
authors.forename: Michel
authors.initials: M
authors.lastname: Samson
authors.forename: Florence
authors.initials: F
authors.lastname: Robert-Gangneux
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007893:Leishmania donovani / Q000276:immunology* / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D008099:Liver / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000097:blood / Q000276:immunology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
chemical_list: C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D018664:Interleukin-12; D007371:Interferon-gamma
references.citation: J Immunol. 1987 Apr 1;138(7):2290-7
references.pmid: 3104456
references.citation: J Cell Mol Med. 2010 Jun;14(6B):1726-39
references.pmid: 19508382
references.citation: Eur J Immunol. 2002 Sep;32(9):2450-9
references.pmid: 12207329
references.citation: Acta Trop. 1994 Apr;56(4):315-25
references.pmid: 8023755
references.citation: Nat Rev Drug Discov. 2008 Oct;7(10):827-40
references.pmid: 18827826
references.citation: Inflamm Bowel Dis. 2010 Jul;16(7):1097-107
references.pmid: 20014018
references.citation: Immunol Cell Biol. 2007 Feb-Mar;85(2):138-47
references.pmid: 17146466
references.citation: Immunol Res. 2012 Apr;52(1-2):89-99
references.pmid: 22392053
references.citation: Pharmacol Ther. 2011 Aug;131(2):179-86
references.pmid: 21356240
references.citation: Int J Immunopathol Pharmacol. 2007 Jul-Sep;20(3):435-45
references.pmid: 17880757
references.citation: J Interferon Cytokine Res. 2007 Sep;27(9):799-808
references.pmid: 17892401
references.citation: Am J Pathol. 2003 Jul;163(1):69-79
references.pmid: 12819012
references.citation: Mucosal Immunol. 2013 Mar;6(2):405-14
references.pmid: 22990621
references.citation: Biochem Biophys Res Commun. 2004 Sep 24;322(3):1086-95
references.pmid: 15336576
references.citation: Oncogene. 2007 Nov 15;26(52):7333-45
references.pmid: 17533374
references.citation: Hepatology. 2012 Oct;56(4):1468-78
references.pmid: 22782692
references.citation: J Immunol. 1995 May 1;154(9):4623-9
references.pmid: 7722314
references.citation: J Intern Med. 2011 Jan;269(1):29-35
references.pmid: 21158975
references.citation: PLoS One. 2012;7(3):e33413
references.pmid: 22457760
references.citation: Int J Parasitol. 2011 Mar;41(3-4):463-9
references.pmid: 21172349
references.citation: Immunol Rev. 2004 Oct;201:239-53
references.pmid: 15361245
references.citation: J Immunol. 1995 Oct 1;155(7):3593-600
references.pmid: 7561058
references.citation: J Immunol. 2012 Jul 1;189(1):287-95
references.pmid: 22661085
references.citation: J Exp Med. 2008 Feb 18;205(2):339-46
references.pmid: 18268038
references.citation: Infect Immun. 2000 Nov;68(11):6294-9
references.pmid: 11035738
references.citation: Dig Dis Sci. 2011 Dec;56(12):3596-601
references.pmid: 21643739
references.citation: Ann Inst Pasteur Immunol. 1987 Sep-Oct;138(5):744-9
references.pmid: 2964247
references.citation: Arthritis Rheum. 2009 Mar;60(3):738-49
references.pmid: 19248109
references.citation: PLoS Negl Trop Dis. 2010 Jun 08;4(6):e703
references.pmid: 20544029
references.citation: Eur J Immunol. 2008 Apr;38(4):1071-81
references.pmid: 18383035
references.citation: Rev Inst Med Trop Sao Paulo. 1987 May-Jun;29(3):131-6
references.pmid: 3324279
references.citation: Allergol Int. 2010 Jun;59(2):143-60
references.pmid: 20414050
references.citation: J Immunol. 2008 Oct 1;181(7):4780-90
references.pmid: 18802081
references.citation: J Immunol. 1993 Jun 1;150(11):4996-5012
references.pmid: 8496601
references.citation: Nat Rev Immunol. 2010 Feb;10(2):103-10
references.pmid: 20081870
references.citation: Nat Rev Rheumatol. 2011 Jun;7(6):321-9
references.pmid: 21519352
references.citation: Indian J Med Res. 2006 Mar;123(3):245-66
references.pmid: 16778308
references.citation: Gastroenterol Clin Biol. 2006 Aug-Sep;30(8-9):1027-32
references.pmid: 17075454
references.citation: Circ Res. 2010 Sep 3;107(5):650-8
references.pmid: 20634488
references.citation: J Clin Invest. 2007 Jun;117(6):1538-49
references.pmid: 17492053
references.citation: J Clin Invest. 1985 Dec;76(6):2066-9
references.pmid: 3935667
references.citation: Ann Rheum Dis. 2012 Apr;71 Suppl 2:i101-4
references.pmid: 22460136
references.citation: Clin Immunol Immunopathol. 1990 Nov;57(2):242-9
references.pmid: 2145107
references.citation: Trends Immunol. 2012 Aug;33(8):389-96
references.pmid: 22609147
references.citation: Mol Cell Biol. 1995 Oct;15(10):5258-67
references.pmid: 7565674
references.citation: Cytokine Growth Factor Rev. 2004 Apr-Jun;15(2-3):87-95
references.pmid: 15110792
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10913-8
references.pmid: 18667700
references.citation: Eur J Immunol. 2010 Feb;40(2):426-36
references.pmid: 19950183
references.citation: Semin Cancer Biol. 1990 Feb;1(1):89-95
references.pmid: 2133114
references.citation: Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1524-32
references.pmid: 19892870
references.citation: PLoS One. 2008 Oct 06;3(10):e3331
references.pmid: 18836528
references.citation: J Exp Med. 2000 Mar 20;191(6):1069-76
references.pmid: 10727469
references.citation: J Clin Invest. 1990 Jun;85(6):1914-24
references.pmid: 2112157
references.citation: J Immunol. 1994 Sep 1;153(5):2052-63
references.pmid: 8051410
references.citation: J Exp Med. 1997 Apr 7;185(7):1231-9
references.pmid: 9104810
references.citation: Infect Immun. 2003 Aug;71(8):4804-7
references.pmid: 12874364
references.citation: Cell Immunol. 1985 Sep;94(2):500-11
references.pmid: 3928173
references.citation: J Immunol. 2008 Feb 15;180(4):2443-9
references.pmid: 18250453
references.citation: Allergy. 2012 Feb;67(2):183-90
references.pmid: 22050307
references.citation: Mucosal Immunol. 2011 Sep;4(5):496-502
references.pmid: 21613987
references.citation: Nat Med. 2010 Jun;16(6):708-12
references.pmid: 20473304
references.citation: BMC Med Genet. 2011 Dec 15;12:162
references.pmid: 22171941
references.citation: Hepatology. 2012 Dec;56(6):2353-62
references.pmid: 22961755
references.citation: Eur J Immunol. 2011 Aug;41(8):2341-8
references.pmid: 21557213
references.citation: Infect Immun. 2003 Apr;71(4):1961-71
references.pmid: 12654814
references.citation: J Infect Dis. 1996 Jun;173(6):1515-8
references.pmid: 8648233
references.citation: Thorac Cardiovasc Surg. 2010 Dec;58(8):443-9
references.pmid: 21113894
references.citation: Immunity. 2005 Nov;23(5):479-90
references.pmid: 16286016