Dataset Information

Mouse mincle: characterization as a model for human mincle and evolutionary implications.

ABSTRACT: Mincle, the macrophage-inducible C-type lectin also known as CLEC-4E, binds to the mycobacterial glycolipid trehalose dimycolate and initiates a signaling cascade by serving as a receptor for Mycobacterium tuberculosis and other pathogenic mycobacterial species. Studies of the biological functions of human mincle often rely on mouse models, based on the assumption that the biological properties of the mouse receptor mimic those of the human protein. Experimental support for this assumption has been obtained by expression of the carbohydrate-recognition domain of mouse mincle and characterization of its interaction with small molecule analogs of trehalose dimycolate. The results confirm that the ligand-binding properties of mouse mincle closely parallel those of the human receptor. These findings are consistent with the conservation of key amino acid residues that have been shown to form the ligand-binding site in human and cow mincle. Sequence alignment reveals that these residues are conserved in a wide range of mammalian species, suggesting that mincle has a conserved function in binding ligands that may include endogenous mammalian glycans or pathogen glycans in addition to trehalose dimycolate.

SUBMITTER: Rambaruth ND

PROVIDER: S-EPMC4533885 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Mouse mincle: characterization as a model for human mincle and evolutionary implications.

Rambaruth Neela D S ND Jégouzo Sabine A F SA Marlor Hayley H Taylor Maureen E ME Drickamer Kurt K

Molecules (Basel, Switzerland) 20150415 4

Mincle, the macrophage-inducible C-type lectin also known as CLEC-4E, binds to the mycobacterial glycolipid trehalose dimycolate and initiates a signaling cascade by serving as a receptor for Mycobacterium tuberculosis and other pathogenic mycobacterial species. Studies of the biological functions of human mincle often rely on mouse models, based on the assumption that the biological properties of the mouse receptor mimic those of the human protein. Experimental support for this assumption has b ...[more]

PMID: 25884549

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Project description:BackgroundCancer cachexia is a complex metabolic disease with unmet medical need. Although many rodent models are available, none are identical to the human disease. Therefore, the development of new preclinical models that simulate some of the physiological, biochemical, and clinical characteristics of the human disease is valuable. The HT-1080 human fibrosarcoma tumour cell line was reported to induce cachexia in mice. Therefore, the purpose of this work was to determine how well the HT-1080 tumour model could recapitulate human cachexia and to examine its technical performance. Furthermore, the efficacy of ghrelin receptor activation via anamorelin treatment was evaluated, because it is one of few clinically validated mechanisms.MethodsFemale severe combined immunodeficient mice were implanted subcutaneously or heterotopically (renal capsule) with HT-1080 tumour cells. The cachectic phenotype was evaluated during tumour development, including body weight, body composition, food intake, muscle function (force and fatigue), grip strength, and physical activity measurements. Heterotopic and subcutaneous tumour histology was also compared. Energy balance was evaluated at standard and thermoneutral housing temperatures in the subcutaneous model. The effect of anamorelin (ghrelin analogue) treatment was also examined.ResultsThe HT-1080 tumour model had excellent technical performance and was reproducible across multiple experimental conditions. Heterotopic and subcutaneous tumour cell implantation resulted in similar cachexia phenotypes independent of housing temperature. Tumour weight and histology was comparable between both routes of administration with minimal inflammation. Subcutaneous HT-1080 tumour-bearing mice presented with weight loss (decreased fat mass and skeletal muscle mass/fibre cross-sectional area), reduced food intake, impaired muscle function (reduced force and grip strength), and decreased spontaneous activity and voluntary wheel running. Key circulating inflammatory biomarkers were produced by the tumour, including growth differentiation factor 15, Activin A, interleukin 6, and TNF alpha. Anamorelin prevented but did not reverse anorexia and weight loss in the subcutaneous model.ConclusionsThe subcutaneous HT-1080 tumour model displays many of the perturbations of energy balance and physical performance described in human cachexia, consistent with the production of key inflammatory factors. Anamorelin was most effective when administered early in disease progression. The HT-1080 tumour model is valuable for studying potential therapeutic targets for the treatment of cachexia.

Dataset Information

Mouse mincle: characterization as a model for human mincle and evolutionary implications.

Publications

Mouse mincle: characterization as a model for human mincle and evolutionary implications.

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