Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0009319 (
colitis
)
19,384
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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
-/-
mice were rescued by triple knockout of the endosomal Toll-like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from
Smcr8
-/-
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
-/-
macrophages.
Smcr8
-/-
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.
...
PMID:Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function. 3044 66
