Abstract
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 slc15a4feeble loss-of-function mouse whose pDC are unresponsive to TLR agonists. slc15a4feeble 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 slc15a4feeble 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 slc15a4feeble versus littermate controls. Taken together, we have identified a role for slc15a4 but not canonical psoriasiform genes in the imiquimod model of psoriasiform dermatitis.
Highlights
Psoriasis is a chronic autoimmune disease affecting approximately 2% of the population[1]
TLR7 sensing via plasmacytoid dendritic cells (pDC) is thought to drive massive IFN-I expression within 6 hours that contributes to the induction of multiple inflammatory markers and histologic alterations in the skin seen within 12–24 hours[19]
The role of pDC and IFN-I in the IMQ psoriasiform dermatitis model is controversial in addition to the source of IFN-I production[4,5,20,22,23]
Summary
Psoriasis is a chronic autoimmune disease affecting approximately 2% of the population[1]. TLR7 and TLR9 sensing is lost in slc15a4 mutant mice resulting in acute loss of IFN-I production secondary to defective pDC within 6 hours post CpG injection[7] and loss of B cell functional responses reported as early as 48 hours after TLR7 and TLR9 stimulation[10]. The physiological role of slc15a4 is likely for protection against pathogens via TLR7/9 sensing We tested this hypothesis and found that slc15a4 was not required for control of acute viremia but was necessary for virus-specific T cell activation and chronic viral clearance[18]. PDC which are responsible for ~50% of all acute IFN-I24 has been implicated in psoriasis[4] and the IMQ psoriasiform model Surprisingly, targeting these cells did not result in any significant changes in the IMQ model[5]
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