The Autoimmune Disorder Susceptibility Gene CLEC16A Restrains NK Cell Function in YTS NK Cell Line and Clec16a Knockout Mice

CLEC16A locus polymorphisms have been associated with several autoimmune diseases. We overexpressed CLEC16A in YTS natural killer (NK) cells and observed reduced NK cell cytotoxicity and IFN-γ release, delayed dendritic cell (DC) maturation, decreased conjugate formation, cell-surface receptor downregulation and increased autophagy. In contrast, siRNA mediated knockdown resulted in increased NK cell cytotoxicity, reversal of receptor expression and disrupted mitophagy. Subcellular localization studies demonstrated that CLEC16A is a cytosolic protein that associates with Vps16A, a subunit of class C Vps-HOPS complex, and modulates receptor expression via autophagy. Clec16a knockout (KO) in mice resulted in altered immune cell populations, increased splenic NK cell cytotoxicity, imbalance of dendritic cell subsets, altered receptor expression, upregulated cytokine and chemokine secretion. Taken together, our findings indicate that CLEC16A restrains secretory functions including cytokine release and cytotoxicity and that a delicate balance of CLEC16A is needed for NK cell function and homeostasis

An extensive phenotypic characterization of the hTNFα transgenic mice

<p>Abstract</p> <p>Background</p> <p>Tumor necrosis factor alpha (TNFα) is implicated in a wide variety of pathological and physiological processes, including chronic inflammatory conditions, coronary artery disease, diabetes, obesity, and cachexia. Transgenic mice expressing human TNFα (hTNFα) have previously been described as a model for progressive rheumatoid arthritis. In this report, we describe extensive characterization of an hTNFα transgenic mouse line.</p> <p>Results</p> <p>In addition to arthritis, these hTNFα transgenic mice demonstrated major alterations in body composition, metabolic rate, leptin levels, response to a high-fat diet, bone mineral density and content, impaired fertility and male sexual function. Many phenotypes displayed an earlier onset and a higher degree of severity in males, pointing towards a significant degree of sexual dimorphism in response to deregulated expression of TNFα.</p> <p>Conclusion</p> <p>These results highlight the potential usefulness of this transgenic model as a resource for studying the progressive effects of constitutively expressed low levels of circulating TNFα, a condition mimicking that observed in a number of human pathological conditions.</p

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 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

An extensive phenotypic characterization of the hTNFα transgenic mice-0

<p><b>Copyright information:</b></p><p>Taken from "An extensive phenotypic characterization of the hTNFα transgenic mice"</p><p>http://www.biomedcentral.com/1472-6793/7/13</p><p>BMC Physiology 2007;7():13-13.</p><p>Published online 10 Dec 2007</p><p>PMCID:PMC2222242.</p><p></p>pendently increased endogenous TNFα in WT and TG mice similarly. WT (open bars) and TG mice (closed bars) were injected with the indicated doses of LPS (μg/mouse) as shown on the X-axis. (A) Human and (B) mouse TNFα levels were measured using ELISA assays. Data are presented as means ± SEM, n = 5 for each genotype and dose combination. ND – non-detectable

An extensive phenotypic characterization of the hTNFα transgenic mice-2

<p><b>Copyright information:</b></p><p>Taken from "An extensive phenotypic characterization of the hTNFα transgenic mice"</p><p>http://www.biomedcentral.com/1472-6793/7/13</p><p>BMC Physiology 2007;7():13-13.</p><p>Published online 10 Dec 2007</p><p>PMCID:PMC2222242.</p><p></p>pendently increased endogenous TNFα in WT and TG mice similarly. WT (open bars) and TG mice (closed bars) were injected with the indicated doses of LPS (μg/mouse) as shown on the X-axis. (A) Human and (B) mouse TNFα levels were measured using ELISA assays. Data are presented as means ± SEM, n = 5 for each genotype and dose combination. ND – non-detectable