Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function

William McAlpine, Lei Sun, Kuan wen Wang, Aijie Liu, Ruchi Jain, Miguel San Miguel, Jianhui Wang, Zhao Zhang, Braden Hayse, Sarah Grace McAlpine, Jin Huk Choi, Xue Zhong, Sara Ludwig, Jamie L Russell, Xiaoming Zhan, Mihwa Choi, Xiaohong Li, Miao Tang, Eva Marie Y. Moresco, Bruce A BeutlerEmre E Turer

Research output: Contribution to journalArticle

2 Citations (Scopus)

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/ 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.

Original languageEnglish (US)
Pages (from-to)E11523-E11531
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number49
DOIs
StatePublished - Dec 4 2018

Fingerprint

Toll-Like Receptors
Autoimmunity
Ligands
Phagosomes
Dextran Sulfate
Mutation
Splenomegaly
Autophagy
Amyotrophic Lateral Sclerosis
Myeloid Cells
Colitis
Endocytosis
Phagocytosis
Macrophages
Cytokines
Inflammation
T-Lymphocytes
Growth

Keywords

  • Inflammation
  • Inflammatory bowel disease
  • Toll-like receptor
  • Vesicle trafficking

ASJC Scopus subject areas

  • General

Cite this

Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function. / McAlpine, William; Sun, Lei; Wang, Kuan wen; Liu, Aijie; Jain, Ruchi; Miguel, Miguel San; Wang, Jianhui; Zhang, Zhao; Hayse, Braden; McAlpine, Sarah Grace; Choi, Jin Huk; Zhong, Xue; Ludwig, Sara; Russell, Jamie L; Zhan, Xiaoming; Choi, Mihwa; Li, Xiaohong; Tang, Miao; Moresco, Eva Marie Y.; Beutler, Bruce A; Turer, Emre E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 49, 04.12.2018, p. E11523-E11531.

Research output: Contribution to journalArticle

McAlpine, W, Sun, L, Wang, KW, Liu, A, Jain, R, Miguel, MS, Wang, J, Zhang, Z, Hayse, B, McAlpine, SG, Choi, JH, Zhong, X, Ludwig, S, Russell, JL, Zhan, X, Choi, M, Li, X, Tang, M, Moresco, EMY, Beutler, BA & Turer, EE 2018, 'Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 49, pp. E11523-E11531. https://doi.org/10.1073/pnas.1814753115
McAlpine, William ; Sun, Lei ; Wang, Kuan wen ; Liu, Aijie ; Jain, Ruchi ; Miguel, Miguel San ; Wang, Jianhui ; Zhang, Zhao ; Hayse, Braden ; McAlpine, Sarah Grace ; Choi, Jin Huk ; Zhong, Xue ; Ludwig, Sara ; Russell, Jamie L ; Zhan, Xiaoming ; Choi, Mihwa ; Li, Xiaohong ; Tang, Miao ; Moresco, Eva Marie Y. ; Beutler, Bruce A ; Turer, Emre E. / Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 49. pp. E11523-E11531.
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AU - McAlpine, William

AU - Sun, Lei

AU - Wang, Kuan wen

AU - Liu, Aijie

AU - Jain, Ruchi

AU - Miguel, Miguel San

AU - Wang, Jianhui

AU - Zhang, Zhao

AU - Hayse, Braden

AU - McAlpine, Sarah Grace

AU - Choi, Jin Huk

AU - Zhong, Xue

AU - Ludwig, Sara

AU - Russell, Jamie L

AU - Zhan, Xiaoming

AU - Choi, Mihwa

AU - Li, Xiaohong

AU - Tang, Miao

AU - Moresco, Eva Marie Y.

AU - Beutler, Bruce A

AU - Turer, Emre E

PY - 2018/12/4

Y1 - 2018/12/4

N2 - 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.

AB - 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.

KW - Inflammation

KW - Inflammatory bowel disease

KW - Toll-like receptor

KW - Vesicle trafficking

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