title: Complement receptor 3 influences toll-like receptor 7/8-dependent inflammation: implications for autoimmune diseases characterized by antibody reactivity to ribonucleoproteins.
abstract: Toll-like receptor (TLR) signaling is an important component in the inflammatory response generated in diseases characterized by autoantibody reactivity to proteins such as SSA/Ro in complex with endogenous nucleic acids. Complement receptor 3 (CR3), a genetic variant of which has been identified as a risk factor in systemic lupus erythematosus, has been shown to induce tolerogenic responses in dendritic cells and suppress TLR4 responses in a murine sepsis model. Accordingly, this study addressed the hypothesis that activation of CR3, influenced by genotype of CD11b, negatively regulates TLR7/8-dependent effector function. Allosteric activation of CD11b via pretreatment with the small molecule, leukadhedrin 1 (LA1), significantly attenuated TLR7/8-induced (hY3 RNA, R848) secretion of TNFα in THP-1 cells and human macrophages isolated from donors homozygous for the ancestral common ITGAM allele at rs1143679. This inhibition was accompanied by profound degradation of the adaptor protein MyD88, an effect not observed with direct inhibition of TLR ligation by an antagonist oligonucleotide. In contrast, the addition of LA1 after incubation with the TLR agonists did not result in MyD88 degradation and subsequent attenuation of TNFα secretion. In TLR7/8-stimulated macrophages isolated from donors heterozygous for the CD11b variant, pretreatment with LA1 did not down-regulate TNFα release. These novel findings support a negative cross-talk between CR3 and TLR pathways likely to be induced by antibodies reactive with ribonucleoproteins and point to the development of CR3-specific agonists as potential therapeutics for diseases such as neonatal lupus.
authors: Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. Joanne.Reed@nyumc.org
authors: Joanne H
authors: JH
authors: Reed
authors: Manish
authors: M
authors: Jain
authors: Kristen
authors: K
authors: Lee
authors: Ekambar R
authors: ER
authors: Kandimalla
authors: Mohd Hafeez
authors: MH
authors: Faridi
authors: Jill P
authors: JP
authors: Buyon
authors: Vineet
authors: V
authors: Gupta
authors: Robert M
authors: RM
authors: Clancy
mesh_terms: D000495:Allosteric Site; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000378:metabolism*; D039481:CD11b Antigen / Q000096:biosynthesis*; D002448:Cell Adhesion; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008957:Models, Genetic; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D039481:CD11b Antigen; D016177:Macrophage-1 Antigen; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D012313:RNA
references: J Med Chem. 2009 Nov 12;52(21):6871-9
references: 19824640
references: Blood. 2006 Aug 1;108(3):947-55
references: 16614246
references: J Autoimmun. 2010 May;34(3):J178-206
references: 20031372
references: J Exp Med. 2005 Dec 5;202(11):1575-85
references: 16330816
references: BMC Mol Biol. 2010 Dec 01;11:90
references: 21122122
references: Genes Dev. 1994 Dec 1;8(23):2891-903
references: 7995526
references: J Biol Chem. 2011 May 13;286(19):17303-10
references: 21454473
references: Ann Rheum Dis. 2010 Oct;69(10):1827-30
references: 20447951
references: J Exp Med. 1997 Jun 2;185(11):1987-95
references: 9166428
references: Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13750-5
references: 17698957
references: J Immunol. 2012 Jun 1;188(11):5293-302
references: 22551553
references: J Eur Acad Dermatol Venereol. 2011 Mar;25(3):271-5
references: 20629846
references: Nat Genet. 2008 Feb;40(2):152-4
references: 18204448
references: J Exp Med. 2005 Nov 7;202(9):1171-7
references: 16260486
references: J Immunol. 2010 Feb 15;184(4):2148-55
references: 20089705
references: J Biol Chem. 2011 Sep 2;286(35):30444-30454
references: 21730058
references: J Immunol. 1990 Oct 15;145(8):2608-15
references: 1976698
references: Circulation. 2012 Jul 3;126(1):76-82
references: 22626746
references: Annu Rev Immunol. 2009;27:339-62
references: 19302044
references: Cell. 2002 Sep 20;110(6):673-87
references: 12297042
references: Hum Mol Genet. 2009 Mar 15;18(6):1171-80
references: 19129174
references: Nat Immunol. 2010 Aug;11(8):734-42
references: 20639876
references: Arthritis Rheum. 2004 Jun;50(6):1861-72
references: 15188363
references: Nature. 2010 Jun 17;465(7300):937-41
references: 20559388
references: Ann Rheum Dis. 2012 Dec;71(12):2028-34
references: 22586164
references: J Med Chem. 2009 Aug 27;52(16):5108-14
references: 19650625
references: Bioorg Med Chem Lett. 2009 Dec 15;19(24):6902-6
references: 19879752
references: Sci Signal. 2011 Sep 6;4(189):ra57
references: 21900205