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|Title:||Role of MyD88 signaling in the imiquimod-induced mouse model of psoriasis: focus on innate myeloid cells||Authors:||Costa, Sara
DeFranco, Anthony L
Lowell, Clifford A
Cassatella, Marco A
|Keywords:||monocytes/macrophages;neutrophils;skin inflammation||Keywords Plus:||INDUCED SKIN INFLAMMATION;DELTA T-CELLS;DENDRITIC CELLS;LANGERHANS CELLS;PLAQUE-FORMATION;MURINE MODEL;CYTOKINES;MICE;MACROPHAGES;NEUTROPHILS||Mesh headings:||Aminoquinolines;Immunity, Innate;Myeloid Cells;Myeloid Differentiation Factor 88;Psoriasis||Secondary Mesh headings:||Animals;Disease Models, Animal;Imiquimod;Interleukin-1beta;Interleukin-23;Mice;Mice, Knockout;Skin||Issue Date:||2017||Publisher:||WILEY||Journal:||Journal of leukocyte biology||Abstract:||
Psoriasis is a chronic skin disease associated with deregulated activation of immune cells and keratinocytes. In this study, we used the imiquimod (IMQ)-induced mouse model of psoriasis to dissect better the contribution of hematopoietic and skin-resident stromal cells to psoriasis development. The comparison of disease development in mice carrying the hematopoietic cell-specific deletion of MyD88 (Myd88fl/flVav-cre+ mice) with mice carrying the total MyD88 deficiency (Myd88-/- mice), we show that the progression of skin and systemic inflammation, as well as of epidermal thickening, was completely dependent on MyD88 expression in hematopoietic cells. However, both Myd88-/- mouse strains developed some degree of epidermal thickening during the initial stages of IMQ-induced psoriasis, even in the absence of hematopoietic cell activation and infiltration into the skin, suggesting a contribution of MyD88-independent mechanisms in skin-resident stromal cells. With the use of conditional knockout mouse strains lacking MyD88 in distinct lineages of myeloid cells (Myd88fl/flLysM-cre+ and Myd88fl/flMRP8-cre+ mice), we report that MyD88 signaling in monocytes and Mϕ, but not in neutrophils, plays an important role in disease propagation and exacerbation by modulating their ability to sustain γδ T cell effector functions via IL-1β and IL-23 production. Overall, these findings add new insights into the specific contribution of skin-resident stromal vs. hematopoietic cells to disease initiation and progression in the IMQ-induced mouse model of psoriasis and uncover a potential novel pathogenic role for monocytes/Mϕ to psoriasis development.
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