Animals; Cytokines (genetics, metabolism); Dermatitis (genetics, metabolism, pathology); Disease Models, Animal; Imiquimod (adverse effects, pharmacology); Inflammation (chemically induced, genetics, metabolism, pathology); Membrane Glycoproteins (analysis, genetics, metabolism); Membrane Transport Proteins (genetics, metabolism); Mice; Mice, Transgenic; Psoriasis (chemically induced, genetics, metabolism, pathology); Skin (metabolism, pathology); Toll-Like Receptor 7 (analysis, genetics, metabolism)
There is competing evidence that plasmacytoid dendritic cells (pDC), the most potent source of IFN-I, may initiate psoriasis. We targeted pDC function using the slc15a4 loss-of-function mouse whose pDC are unresponsive to TLR agonists. slc15a4 treated with the topical TLR7-agonist imiquimod (IMQ) demonstrated decreased epidermal thickening 24 hours post-treatment which was more pronounced by day 5 as compared to wildtype mice. These findings were specific to the acute IMQ model and not the protracted IL23 model that drives inflammation downstream of TLR activation. Systemically, slc15a4 was required for IMQ-induced weight loss and cutaneous accumulation of CD4+ and Siglec H+, but not CD11b+ cells. Consistent with this phenotype and the function of slc15a4, induction of IFN-I was virtually absent systemically and via cutaneous gene expression. Induction of other inflammatory cytokines (cytokine storm) was modestly blunted in slc15a4 except for inflammasome-associated genes consistent with slc15a4 being required for TLR7-mediated (but not inflammasome-mediated) inflammation downstream of IMQ. Surprisingly, only IFN-I gene expression was suppressed within IMQ-treated skin. Other genes including conserved psoriasiform trademark gene expression were augmented in slc15a4 versus littermate controls. Taken together, we have identified a role for slc15a4 but not canonical psoriasiform genes in the imiquimod model of psoriasiform dermatitis.
Digital Object Identifier (DOI)
Scientific reports, Volume 294, Issue 16, 2018, pages 6450-.
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Griffith, A., Zaidi, A., Pietro, A., Hadiono, M., Yang, J., Davis, R., & Popkin, D. (2018). A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice. Scientific Reports, 8(1). https://doi.org/10.1038/s41598-018-32668-9