Back to Search
Start Over
Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Dec 04; Vol. 115 (49), pp. E11523-E11531. Date of Electronic Publication: 2018 Nov 15. - Publication Year :
- 2018
-
Abstract
- The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of-function mutations of Smcr8 or C9orf72 in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of C9ORF72 However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in Smcr8 <superscript> -/- </superscript> mice were rescued by triple knockout of the endosomal Toll-like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from Smcr8 <superscript> -/- </superscript> mice produced excessive inflammatory cytokines in response to endocytosed TLR3, TLR7, or TLR9 ligands administered in the growth medium and in response to TLR2 or TLR4 ligands internalized by phagocytosis. These defects likely stem from prolonged TLR signaling caused by accumulation of LysoTracker-positive vesicles and by delayed phagosome maturation, both of which were observed in Smcr8 <superscript> -/- </superscript> macrophages. Smcr8 <superscript> -/- </superscript> mice also showed elevated susceptibility to dextran sodium sulfate-induced colitis, which was not associated with increased TLR3, TLR7, or TLR9 signaling. Deficiency of WDR41 phenocopied loss of SMCR8. Our findings provide evidence that excessive endosomal TLR signaling resulting from prolonged ligand-receptor contact causes inflammatory disease in SMCR8-deficient mice.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Animals
Autoimmune Diseases genetics
Autoimmune Diseases metabolism
Autophagy-Related Proteins
C9orf72 Protein genetics
Carrier Proteins genetics
Colitis chemically induced
Dextran Sulfate
Gene Expression Regulation
Hematopoiesis genetics
Intracellular Signaling Peptides and Proteins genetics
Mice
Mice, Knockout
Mutation
Signal Transduction immunology
Toll-Like Receptors genetics
C9orf72 Protein metabolism
Carrier Proteins metabolism
Inflammation metabolism
Intracellular Signaling Peptides and Proteins metabolism
Toll-Like Receptors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 115
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 30442666
- Full Text :
- https://doi.org/10.1073/pnas.1814753115