Dynamics and Transcriptomics of Skin Dendritic Cells and Macrophages in an Imiquimod-Induced, Biphasic Mouse Model of Psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disease of unknown etiology. Previous studies showed that short-term, 5–7 d-long application of imiquimod (IMQ), a TLR7 agonist, to the skin of mice triggers a psoriasis-like inflammation. In the current study, by applying IMQ for 14 consecutive d, we established an improved mouse psoriasis-like model in that it recapitulated many of the clinical and cellular hallmarks observed in human patients during both the early-onset and the late-stable phase of psoriasis. Although macrophages and dendritic cells (DCs) have been proposed to drive the psoriatic cascade, their largely overlapping phenotype hampered studying their respective role. Based on our ability to discriminate Langerhans cells (LCs), conventional DCs, monocytes, monocyte-derived DCs, macrophages, and plasmacytoid DCs in the skin, we addressed their dynamics during both phases of our biphasic psoriasis-like model. Plasmacytoid DCs were not detectable during the whole course of IMQ treatment. During the early phase, neutrophils infiltrated the epidermis, whereas monocytes and monocyte-derived DCs were predominant in the dermis. During the late phase, LCs and macrophage numbers transiently increased in the epidermis and dermis, respectively. LC expansion resulted from local proliferation, a conclusion supported by global transcriptional analysis. Genetic depletion of LCs permitted to evaluate their function during both phases of the biphasic psoriasis-like model and demonstrated that their absence resulted in a late phase that is associated with enhanced neutrophil infiltration. Therefore, our data support an anti-inflammatory role of LCs during the course of psoriasis-like inflammation.

Effects of Imiquimod on Hair Follicle Stem Cells and Hair Cycle Progression

“…Moreover, dermal resident macrophages were shown to express IL10 under steady-state condition thus playing an anti-inflammatory and scavenging role in the skin (Tamoutounour et al, 2013). However, under inflammatory conditions, monocytederived macrophages infiltrate the skin and support the production of cytokines like TNFa, IL-6, IL-12 and IFNs (Chen et al, 2015;Drobits et al, 2012;Morimura et al, 2016;Terhorst et al, 2015). Injury-induced CCL2 production by the skin was recently shown to induce macrophage infiltration and TNFα production, ultimately resulting in hair cycle induction (Chen et al, 2015).…”

“…In humans, the 5% IMQ cream formulation Aldara® is frequently used for the treatment of genital warts, actinic keratosis and superficial basal cell carcinomas with very high response rates (Bath-Hextall et al, 2014;de Macedo et al, 2015;Gollnick et al, 2005;Peris et al, 2014). In mice and humans topical application of IMQ results in the activation of the interfollicular epidermis (IFE), upregulation of MHC-II on keratinocytes, hyperproliferation and parakeratosis (Flutter and Nestle, 2013), as well as a strong skin inflammation characterized by the infiltration of several immune cells such as plasmacytoid dendritic cells (Drobits et al, 2012;Kalb et al, 2012;Palamara et al, 2004), mast cells (Heib et al 2007), monocytes (Terhorst et al, 2015) and T cells and activation of the IL23/IL17/IL22 axis (Heib et al, 2007;Riol-Blanco et al, 2014;van der Fits et al, 2009).…”

Near-Infrared 1064 nm Laser Modulates Migratory Dendritic Cells To Augment the Immune Response to Intradermal Influenza Vaccine

“…Terhorst et al . observed that skin micropores generated by ablative fractional laser using the P.L.E.A.S.E.® (Precise Laser Epidermal System) device enhanced the anti-tumor immune responses induced by prophylactic and therapeutic cancer vaccines (24). The local inflammatory milieu created by the death of keratinocytes during skin laser microporation was similarly responsible for activation of XCR1 + DCs, thereby inducing tumor antigen-specific CD8 + and CD4 + T cell responses.…”

Multiple Immunosuppressive Effects of CpG-c41 on Intracellular TLR-Mediated Inflammation

“…Attenuates IMQ-Induced Psoriasis-Like Inflammation In Vivo. Studies have increasingly shown that PAMPs are the precipitating factor for psoriasis, and a psoriasis-like animal model has been developed [26,27]. We investigated the effects of CpG-c41 in this model.…”