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: Joanne H Reed, Manish Jain, Kristen Lee, Ekambar R Kandimalla, Mohd Hafeez Faridi, Jill P Buyon, Vineet Gupta, Robert M Clancy
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 13 Pg. 9077-83 (Mar 29 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23386618 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• CD11b Antigen
• Macrophage-1 Antigen
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Toll-Like Receptor 7
• Toll-Like Receptor 8
• RNA

Topics

• Allosteric Site
• Anti-Inflammatory Agents (pharmacology)
• Autoimmune Diseases (metabolism)
• CD11b Antigen (biosynthesis)
• Cell Adhesion
• Down-Regulation
• Gene Expression Regulation
• Heterozygote
• Humans
• Inflammation
• Leukocytes, Mononuclear (cytology, metabolism)
• Lupus Erythematosus, Systemic (metabolism)
• Macrophage-1 Antigen (metabolism)
• Macrophages (cytology, metabolism)
• Models, Genetic
• Myeloid Differentiation Factor 88 (metabolism)
• RNA (metabolism)
• Signal Transduction
• Toll-Like Receptor 7 (metabolism)
• Toll-Like Receptor 8 (metabolism)