| Autor: |
Griffith AD; Department of Dermatology, Case Western Reserve University Hospitals, Cleveland, OH, 44106, USA., Zaidi AK; Department of Dermatology, Case Western Reserve University Hospitals, Cleveland, OH, 44106, USA., Pietro A; Department of Dermatology, Case Western Reserve University Hospitals, Cleveland, OH, 44106, USA., Hadiono M; Department of Dermatology, Case Western Reserve University Hospitals, Cleveland, OH, 44106, USA., Yang JS; Department of Dermatology, Case Western Reserve University Hospitals, Cleveland, OH, 44106, USA., Davis R; Department of Dermatology, Case Western Reserve University Hospitals, Cleveland, OH, 44106, USA., Popkin DL; Department of Dermatology, Case Western Reserve University Hospitals, Cleveland, OH, 44106, USA. daniel.popkin@case.edu.; Departments of Dermatology, Pathology, Molecular Biology and Microbiology, Case Western Reserve University Hospitals, Cleveland, OH, 44106, USA. daniel.popkin@case.edu. |
| Abstrakt: |
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 feeble loss-of-function mouse whose pDC are unresponsive to TLR agonists. slc15a4 feeble 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 feeble 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 feeble versus littermate controls. Taken together, we have identified a role for slc15a4 but not canonical psoriasiform genes in the imiquimod model of psoriasiform dermatitis. |
