Role of MyD88 signaling in the imiquimod-induced mouse model of psoriasis: focus on innate myeloid cells

J Leukoc Biol. 2017 Sep;102(3):791-803. doi: 10.1189/jlb.3MA0217-054RR. Epub 2017 Jun 22.

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.

Keywords: monocytes/macrophages; neutrophils; skin inflammation.

MeSH terms

  • Aminoquinolines / toxicity*
  • Animals
  • Disease Models, Animal
  • Imiquimod
  • Immunity, Innate / drug effects*
  • Immunity, Innate / genetics
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Interleukin-23 / genetics
  • Interleukin-23 / immunology
  • Mice
  • Mice, Knockout
  • Myeloid Cells / immunology*
  • Myeloid Cells / pathology
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology*
  • Psoriasis / chemically induced*
  • Psoriasis / genetics
  • Psoriasis / immunology*
  • Psoriasis / pathology
  • Skin / immunology
  • Skin / pathology

Substances

  • Aminoquinolines
  • IL1B protein, mouse
  • Interleukin-1beta
  • Interleukin-23
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Imiquimod