Complement receptor 3 influences toll-like receptor 7/8-dependent inflammation: Implications for autoimmune diseases characterized by antibody reactivity to ribonucleoproteins

Joanne H. Reed, Manish Jain, Kristen Lee, Ekambar R. Kandimalla, Mohd Hafeez Faridi, Jill P. Buyon, Vineet Gupta, Robert M. Clancy

Research output: Contribution to journalArticlepeer-review

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 TNF α 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 betweenCR3andTLRpathways 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.

Original languageEnglish (US)
Pages (from-to)9077-9083
Number of pages7
JournalJournal of Biological Chemistry
Volume288
Issue number13
DOIs
StatePublished - Mar 29 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Complement receptor 3 influences toll-like receptor 7/8-dependent inflammation: Implications for autoimmune diseases characterized by antibody reactivity to ribonucleoproteins'. Together they form a unique fingerprint.

Cite this