Contribution of In Vivo and Organotypic 3D Models to Understanding the Role of Macrophages and Neutrophils in the Pathogenesis of Psoriasis

Abstract

Psoriasis, a common chronic immune-mediated skin disease, is histologically characterized by a rapid keratinocyte turnover and differentiation defects. Key insights favor the idea that T cells are not the only key actors involved in the inflammatory process. Innate immune cells, more precisely neutrophils and macrophages, provide specific signals involved in the initiation and the maintenance of the pathogenesis. Current data from animal models and, to a lesser extent, three-dimensional in vitro models have confirmed the interest in leaning towards other immune cell types as a potential new cellular target for the treatment of the disease. Although these models do not mimic the complex phenotype nor all human features of psoriasis, their development is necessary and essential to better understand reciprocal interactions between skin cells and innate immune cells and to emphasize the crucial importance of the local lesional microenvironment. In this review, through the use of in vivo and 3D organotypic models, we aim to shed light on the crosstalk between epithelial and immune components and to discuss the role of secreted inflammatory molecules in the development of this chronic skin disease.

Figure 1

Location and function of macrophages and neutrophils in healthy (a) and psoriatic (b) skin. Langerhans cells and CD8 T cells are present in healthy epidermis, while CD4 T cells, as well as macrophages, NK T cells, dermal dendritic cells (DCs), and plasmacytoid dendritic cells (pDCs), are found in the dermis mainly composed by fibroblasts and extracellular matrix. Immune cell infiltrates are present in the psoriatic epidermis, consisting of activated CD4 and CD8 T cells and clusters of Munro's abscess in the stratum corneum. In the dermis, the activation of cells of both innate and adaptive promotes an inflammatory response. Neutrophils and macrophages (differentiated from monocytes) infiltrate the dermis and secrete proinflammatory cytokines. The crosstalk between skin cells and immune cells leads to a complex inflammatory response and contributes to the development of a pathological epithelial phenotype. NET: neutrophil extracellular trap; Treg: regulatory T cell; M: macrophage.