Oral Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Langerhans cells are an essential cellular intermediary in SHARPIN deficient chronic dermatitis (#34)

Holly Anderton 1 2 , Michael Chopin 1 2 , Caleb A Dawson 1 2 , Stephen L Nutt 1 2 , Natasha Silke 1 2 , Najoua Lalaoui 1 2 , John Silke 1 2
  1. Walter and Eliza Hall Institute (WEHI), Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia

SHARPIN, a linear ubiquitin-chain assembly complex (LUBAC) component, regulates signalling from TNF superfamily and pattern recognition receptors. An inactivating mutation in Sharpin in mice results in TNF-mediated dermatitis. Blocking cell death prevents the inflammatory phenotype, implicating TNFR1-induced cell death in causing the skin disease. However, the source of TNF driving the dermatitis is unknown. Immune cells are a potent source of TNF in vivo and feature prominently in the skin pathology; however, T-cells, B-cells, and eosinophils are dispensable for the skin phenotype. To investigate the possible pathogenic contribution of other immune cells to the cutaneous phenotype, we used the transgenic Diphtheria Toxin Receptor system to specifically ablate immune cell subsets in vivo. We found that systemic depletion of CCR2+ cells delayed the onset of the disease but did not prevent dermatitis. In contrast, depletion of Langerin+ cells results in a highly significant reduction in clinical severity. We, therefore, crossed the Sharpin mutant mice to a novel mouse strain that is largely absent LCs. These mice had no macroscopic dermatitis at the typical endpoint. Remarkably, we also observed a reduction in the severity of the systemic inflammatory phenotype when LCs were absent. Transplant of Sharpin mutant LCs that are also absent TNF into LC depleted Sharpin mutant mice did not reconstitute the skin phenotype. These results demonstrate a direct, inflammatory role for LCs independent of their well-characterised T-cell regulatory functions. We show that LCs play a crucial role in promoting a cell death-driven, TNF mediated dermatitis phenotype, indicating that LCs can be a cellular source of pathogenic TNF in skin disease.

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