CLEC16A regulates splenocyte and NK cell function in part through MEK signaling

CLEC16A is implicated in multiple autoimmune diseases. We generated Clec16a inducible knockout (KO) mice to examine the functional link between CLEC16A auto-inflammation and autoimmunity. Clec16a KO mice exhibited weight loss and thymic and splenic atrophy. Mitochondrial potential was lowered in KO...

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Bibliographic Details
Published in:PloS one 2018-09, Vol.13 (9), p.e0203952-e0203952
Main Authors: Pandey, Rahul, Bakay, Marina, Hain, Heather S, Strenkowski, Bryan, Elsaqa, Barakat Z B, Roizen, Jeffrey D, Kushner, Jake A, Orange, Jordan S, Hakonarson, Hakon
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Animals
Arthritis
Atrophy
Autoimmune diseases
Autophagy
Biology and Life Sciences
Blotting, Western
Cytokines - metabolism
Cytotoxicity
Diabetes
Disease
Endocrinology
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Gene expression
Genomics
Hospitals
Immune system
Immunosuppressive agents
Insects
Killer cells
Killer Cells, Natural - metabolism
Killer Cells, Natural - physiology
Kinases
Laboratories
Lectins, C-Type - physiology
Lymphocytes
Lymphocytes B
Lymphocytes T
MAP Kinase Signaling System - physiology
Medicine
Medicine and Health Sciences
Membrane Potential, Mitochondrial
Mice
Mice, Knockout
Mitochondria
Mitophagy
Monosaccharide Transport Proteins - physiology
Multiple sclerosis
Natural killer cells
Pathogenesis
Pediatrics
Proteins
Research and Analysis Methods
Single nucleotide polymorphisms
Spleen
Spleen - cytology
Spleen - metabolism
Spleen - physiology
Splenocytes
Thymus
Toxicity
Weight loss
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Summary:CLEC16A is implicated in multiple autoimmune diseases. We generated Clec16a inducible knockout (KO) mice to examine the functional link between CLEC16A auto-inflammation and autoimmunity. Clec16a KO mice exhibited weight loss and thymic and splenic atrophy. Mitochondrial potential was lowered in KO mice splenocytes resulting in aggregation of unhealthy mitochondria in B, T, and NK cells. In Clec16a KO mice we detected disrupted mitophagy in splenic B and T cells. NK cells from Clec16a KO mice exhibited increased cytotoxicity. Incomplete mitophagy was attenuated with PI3K and/or MEK inhibition in Clec16a KO mice. Our results demonstrate a functional link between CLEC16A and disrupted mitophagy in immune cells and show that incomplete mitophagy predisposes the KO mice to inflammation. Taken together, loss of function variants in CLEC16A that are associated with decreased CLEC16A expression levels may contribute to inflammation in autoimmunity through disrupted mitophagy. Drugs modulating mitophagy reverse the process and may be effective in treating and preventing autoimmunity in individuals with risk associated CLEC16A variants.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0203952