title: Mannose receptor interacts with Fc receptors and is critical for the development of crescentic glomerulonephritis in mice.
abstract: Crescentic glomerulonephritis (CGN), which frequently results in acute and chronic kidney disease, is characterized by and dependent on glomerular infiltration by macrophages. The mannose receptor (MR) is a pattern recognition receptor implicated in the uptake of endogenous and microbial ligands by macrophages, mesangial cells (MCs), and selected endothelial cells. It is upregulated on alternatively activated macrophages (i.e., macrophages associated with tissue repair and humoral immunity) and involved in antigen presentation to T cells. We used the mouse model of nephrotoxic nephritis to investigate the role of MR in CGN. Our results demonstrate what we believe to be a novel role for MR in the promotion of CGN that is independent of adaptive immune responses. MR-deficient (Mr-/-) mice were protected from CGN despite generating humoral and T cell responses similar to those of WT mice, but they demonstrated diminished macrophage and MC Fc receptor-mediated (FcR-mediated) functions, including phagocytosis and Fc-mediated oxygen burst activity. Mr-/- MCs demonstrated augmented apoptosis compared with WT cells, and this was associated with diminished Akt phosphorylation. Macrophage interaction with apoptotic MCs induced a noninflammatory phenotype that was more marked in Mr-/- macrophages than in WT macrophages. Our results demonstrate that MR augments Fc-mediated function and promotes MC survival. We suggest that targeting MR may provide an alternative therapeutic approach in CGN while minimizing the impact on adaptive immune responses, which are affected by conventional immunosuppressive approaches.
authors.affiliation: Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Konstantia-Maria
authors.initials: KM
authors.lastname: Chavele
authors.forename: Luisa
authors.initials: L
authors.lastname: Martinez-Pomares
authors.forename: Jan
authors.initials: J
authors.lastname: Domin
authors.forename: Samantha
authors.initials: S
authors.lastname: Pemberton
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Haslam
authors.forename: Anne
authors.initials: A
authors.lastname: Dell
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
mesh_terms: D000818:Animals; D017209:Apoptosis; D005260:Female; D005786:Gene Expression Regulation; D005921:Glomerulonephritis / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D010587:Phagocytosis; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011961:Receptors, Fc / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011961:Receptors, Fc; D010100:Oxygen
references.citation: Nat Genet. 2008 May;40(5):553-9
references.pmid: 18443593
references.citation: J Am Soc Nephrol. 2007 Apr;18(4):1167-79
references.pmid: 17314328
references.citation: N Engl J Med. 2004 Mar 4;350(10):971-80
references.pmid: 14999109
references.citation: Kidney Int. 2002 Dec;62(6):2087-96
references.pmid: 12427132
references.citation: J Exp Med. 1999 Jun 21;189(12):1961-72
references.pmid: 10377192
references.citation: Infect Immun. 2003 Jan;71(1):437-45
references.pmid: 12496194
references.citation: Kidney Int. 2003 Jan;63(1):83-95
references.pmid: 12472771
references.citation: Methods Enzymol. 2006;415:59-86
references.pmid: 17116468
references.citation: J Immunol. 2008 Jan 15;180(2):706-15
references.pmid: 18178808
references.citation: J Clin Invest. 1997 Nov 1;100(9):2263-75
references.pmid: 9410904
references.citation: J Immunol. 2003 Sep 1;171(5):2610-5
references.pmid: 12928413
references.citation: Nephrol Dial Transplant. 1998;13 Suppl 1:10-5
references.pmid: 9507491
references.citation: J Biol Chem. 2002 Nov 1;277(44):41613-23
references.pmid: 12196537
references.citation: Immunity. 2007 Aug;27(2):308-20
references.pmid: 17681821
references.citation: Nephrol Dial Transplant. 2004 Nov;19(11):2761-8
references.pmid: 15353578
references.citation: Am J Pathol. 2005 Nov;167(5):1207-19
references.pmid: 16251406
references.citation: J Leukoc Biol. 2008 Aug;84(2):389-96
references.pmid: 18483206
references.citation: J Am Soc Nephrol. 1999 Apr;10(4):752-9
references.pmid: 10203359
references.citation: J Immunol. 2007 Apr 15;178(8):4975-83
references.pmid: 17404279
references.citation: Nat Rev Immunol. 2003 Jan;3(1):23-35
references.pmid: 12511873
references.citation: J Clin Invest. 1994 Nov;94(5):2105-16
references.pmid: 7962557
references.citation: Nat Immunol. 2005 Dec;6(12):1191-7
references.pmid: 16369558
references.citation: Kidney Int. 2005 Feb;67(2):566-75
references.pmid: 15673304
references.citation: Clin Exp Immunol. 2002 Dec;130(3):459-66
references.pmid: 12452836
references.citation: Infect Immun. 2003 Nov;71(11):6213-21
references.pmid: 14573639
references.citation: Cell. 2002 Dec 27;111(7):927-30
references.pmid: 12507420
references.citation: Kidney Int. 2001 Jan;59(1):304-16
references.pmid: 11135084
references.citation: J Immunol. 2001 Jun 1;166(11):6820-8
references.pmid: 11359841
references.citation: Blood. 2008 Jul 1;112(1):64-72
references.pmid: 18434610
references.citation: Kidney Int. 1997 Nov;52(5):1224-31
references.pmid: 9350645
references.citation: J Immunol. 1996 Apr 15;156(8):2964-71
references.pmid: 8609417
references.citation: J Exp Med. 2006 Mar 20;203(3):789-97
references.pmid: 16520389
references.citation: Science. 2006 Aug 4;313(5787):670-3
references.pmid: 16888140
references.citation: Kidney Int. 1999 May;55(5):1639-71
references.pmid: 10231428
references.citation: J Leukoc Biol. 1995 Apr;57(4):687-91
references.pmid: 7536792
references.citation: Eur J Immunol. 2006 May;36(5):1074-82
references.pmid: 16619293
references.citation: J Immunol. 2000 Feb 15;164(4):2110-9
references.pmid: 10657665
references.citation: Biochemistry. 1985 Sep 24;24(20):5551-7
references.pmid: 4074713
references.citation: J Am Soc Nephrol. 2007 Jul;18(7):2180-8
references.pmid: 17582159
references.citation: J Clin Invest. 2002 Oct;110(7):955-63
references.pmid: 12370273
references.citation: Proc Natl Acad Sci U S A. 1970 Jul;66(3):975-82
references.pmid: 4193390
references.citation: Anal Biochem. 2008 Apr 15;375(2):163-72
references.pmid: 18249181
references.citation: Kidney Int. 1995 Jan;47(1):114-21
references.pmid: 7731136
references.citation: Am J Pathol. 2003 May;162(5):1677-83
references.pmid: 12707052
references.citation: J Leukoc Biol. 2007 May;81(5):1188-96
references.pmid: 17261547
references.citation: Science. 2002 Mar 8;295(5561):1898-901
references.pmid: 11884756