Transmembrane Mutations in Toll-like Receptor 9 Bypass the Requirement for Ectodomain Proteolysis and Induce Fatal Inflammation

• Published in: Immunity (Cambridge, Mass.) Vol. 35; no. 5; pp. 721 - 732
• Main Authors: Mouchess, Maria L., Arpaia, Nicholas, Souza, Gianne, Barbalat, Roman, Ewald, Sarah E., Lau, Laura, Barton, Gregory M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.11.2011; Elsevier Limited
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Autoimmunity - genetics; Autoimmunity - immunology; B-Lymphocytes - immunology; Cell Membrane - metabolism; Dendritic Cells - immunology; Deoxyribonucleic acid; Disease; DNA; Gene Expression; Genes, Lethal; HEK293 Cells; Humans; Immune system; Inflammation - genetics; Inflammation - immunology; Ligands; Lupus; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Mutation; Protein Binding; Protein Structure, Tertiary - genetics; Protein Transport; Proteolysis; Receptor, Interferon alpha-beta - deficiency; Receptor, Interferon alpha-beta - immunology; Signal Transduction; Software; T-Lymphocytes - immunology; Toll-Like Receptor 9 - chemistry; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2011.10.009

Recognition of nucleic acids as a signature of infection by Toll-like receptors (TLRs) 7 and 9 exposes the host to potential self-recognition and autoimmunity. It has been proposed that intracellular compartmentalization is largely responsible for reliable self versus nonself discrimination by these receptors. We have previously shown that TLR9 and TLR7 require processing prior to activation, which may further reinforce receptor compartmentalization and tolerance to self, yet this possibility remains untested. Here we report that residues within the TLR9 transmembrane (TM) region conferred the requirement for ectodomain proteolysis. TLR9 TM mutants responded to extracellular DNA, and mice expressing such receptors died from systemic inflammation and anemia. This inflammatory disease did not require lymphocytes and appeared to require recognition of self-DNA by dendritic cells. To our knowledge, these results provide the first demonstration that TLR-intrinsic mutations can lead to a break in tolerance. [Display omitted] ► TLR9 transmembrane mutations allow activation independent of ectodomain processing ► TLR9 transmembrane mutants can no longer discriminate between foreign and self DNA ► Mice expressing TLR9 mutants develop systemic inflammation ► TLR9-mediated disease is independent of lymphocytes but requires dendritic cells