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- W2938998366 abstract "The linear ubiquitin-chain assembly complex (LUBAC), of which SHARPIN is a component, regulates signalling pathways from TNF superfamily and pattern recognition receptors. A spontaneous loss of function mutation in Sharpin is designated cpdm due to a prominent chronic proliferative dermatitis (CPD) phenotype. Loss of TNF or TNFR1 prevents the dermatitis and crosses to Ripk3-/-, Mlkl-/- and Caspase8+/- show that blocking cell death also limits the inflammatory phenotypes, implicating TNFR1 induced cell death as a driver of the CPD. However, little is known about which cells are the source of TNF. Immune cells can be a potent source of TNF in-vivo and feature prominantly in the CPD pathology, yet T-cells and B-cells play no significant role in the phenotype. To investigate the possible pathogenic contribution of other immune cells to the Sharpincpdm cutaneous phenotype we utilised the transgenic Diphtheria Toxin Receptor system to ablate particular immune cell subsets in-vivo. We found that chronic systemic depletion of CD11b+or CCR2+ cells in Sharpincpdm mice delays onset of disease but does not prevent progressive dermatitis, however, a similar depletion of Langerhans cells (LCs), results in a dramatic reduction in clinical severity at the typical Sharpincpdm endpoint. We therefore crossed the Sharpincpdm mice to a novel mouse strain with a defect that prevents LCs from replicating and populating the epidermis and found that these mice had no macroscopic dermatitis at the Sharpin endpoint. Although LCs are often believed to inhibit T-cell activation this work demonstrates that they can play a significant pro-inflammatory role in the TNF dependent, cell death mediated skin disease that arises in Sharpin mutant mice. Our work indicates that they are the cellular source of pathogenic TNF in the Sharpincpdm skin, and implies that they might play a similar T-cell independent role in other inflammatory skin diseases." @default.
- W2938998366 created "2019-04-25" @default.
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- W2938998366 date "2019-05-01" @default.
- W2938998366 modified "2023-09-25" @default.
- W2938998366 title "506 Langerhans cells drive TNF induced chronic proliferative dermatitis in SHARPIN deficient mice" @default.
- W2938998366 doi "https://doi.org/10.1016/j.jid.2019.03.582" @default.
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