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      A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice

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          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 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.

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          Most cited references27

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          Plasmacytoid predendritic cells initiate psoriasis through interferon-α production

          Psoriasis is one of the most common T cell–mediated autoimmune diseases in humans. Although a role for the innate immune system in driving the autoimmune T cell cascade has been proposed, its nature remains elusive. We show that plasmacytoid predendritic cells (PDCs), the natural interferon (IFN)-α–producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN-α early during disease formation. In a xenograft model of human psoriasis, we demonstrate that blocking IFN-α signaling or inhibiting the ability of PDCs to produce IFN-α prevented the T cell–dependent development of psoriasis. Furthermore, IFN-α reconstitution experiments demonstrated that PDC-derived IFN-α is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN-α represent potential early targets for the treatment of psoriasis.
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            The Inflammatory Response in Psoriasis: a Comprehensive Review.

            Psoriasis is a chronic inflammatory autoimmune disease characterized by an excessively aberrant hyperproliferation of keratinocytes. The pathogenesis of psoriasis is complex and the exact mechanism remains elusive. However, psoriasis is thought to result from a combination of genetic, epigenetic, and environmental influences. Recent studies have identified that epigenetic factors including dysregulated DNA methylation levels, abnormal histone modification and microRNAs expressions are involved in the development of psoriasis. The interplay of immune cells and cytokines is another critical factor in the pathogenesis of psoriasis. These factors or pathways include Th1/Th2 homeostasis, the Th17/Treg balance and the IL-23/Th17 axis. Th17 is believed particularly important in psoriasis due to its pro-inflammatory effects and its involvement in an integrated inflammatory loop with dendritic cells and keratinocytes, contributing to an overproduction of antimicrobial peptides, inflammatory cytokines, and chemokines that leads to amplification of the immune response. In addition, other pathways and signaling molecules have been found to be involved, including Th9, Th22, regulatory T cells, γδ T cells, CD8(+) T cells, and their related cytokines. Understanding the pathogenesis of psoriasis will allow us to develop increasingly efficient targeted treatment by blocking relevant inflammatory signaling pathways and molecules. There is no cure for psoriasis at the present time, and much of the treatment involves managing the symptoms. The biologics, while lacking the adverse effects associated with some of the traditional medications such as corticosteroids and methotrexate, have their own set of side effects, which may include reactivation of latent infections. Significant challenges remain in developing safe and efficacious novel targeted therapies that depend on a better understanding of the immunological dysfunction in psoriasis.
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              Inflammasome-independent regulation of IL-1-family cytokines.

              Induction, production, and release of proinflammatory cytokines are essential steps to establish an effective host defense. Cytokines of the interleukin-1 (IL-1) family induce inflammation and regulate T lymphocyte responses while also displaying homeostatic and metabolic activities. With the exception of the IL-1 receptor antagonist, all IL-1 family cytokines lack a signal peptide and require proteolytic processing into an active molecule. One such unique protease is caspase-1, which is activated by protein platforms called the inflammasomes. However, increasing evidence suggests that inflammasomes and caspase-1 are not the only mechanism for processing IL-1 cytokines. IL-1 cytokines are often released as precursors and require extracellular processing for activity. Here we review the inflammasome-independent enzymatic processes that are able to activate IL-1 cytokines, paying special attention to neutrophil-derived serine proteases, which subsequently induce inflammation and modulate host defense. The inflammasome-independent processing of IL-1 cytokines has important consequences for understanding inflammatory diseases, and it impacts the design of IL-1-based modulatory therapies.
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                Author and article information

                Contributors
                daniel.popkin@case.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                27 September 2018
                27 September 2018
                2018
                : 8
                : 14451
                Affiliations
                [1 ]ISNI 0000 0001 2164 3847, GRID grid.67105.35, Department of Dermatology, , Case Western Reserve University Hospitals, ; Cleveland, OH 44106 USA
                [2 ]ISNI 0000 0001 2164 3847, GRID grid.67105.35, Departments of Dermatology, Pathology, Molecular Biology and Microbiology, , Case Western Reserve University Hospitals, ; Cleveland, OH 44106 USA
                Article
                32668
                10.1038/s41598-018-32668-9
                6160456
                94dad0b7-4d7f-4c4c-ba43-e31420222dda
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 June 2018
                : 4 September 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000069, U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS);
                Award ID: P30AR039750
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000738, U.S. Department of Veterans Affairs (VA);
                Award ID: IBX002719A
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100001946, American Skin Association;
                Award ID: Carson Scholars Fund
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100006108, U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS);
                Award ID: UL1TR000439
                Award Recipient :
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