Misbehaving macrophages in the pathogenesis of psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disease unique to humans. In this issue of the JCI, 2 studies of very different mouse models of psoriasis both report that macrophages play a key role in inducing psoriasis-like skin disease. Psoriasis is clearly a polygenic, inherited disease of uncontrolled cutaneous inflammation. The debate that currently rages in the field is whether psoriasis is a disease of autoreactive T cells or whether it reflects an intrinsic defect within the skin--or both. However, these questions have proven difficult to dissect using molecular genetic tools. In the current studies, the authors have used 2 different animal models to address the role of macrophages in disease pathogenesis: Wang et al. use a mouse model in which inflammation is T cell dependent, whereas the model used by Stratis et al. is T cell independent (see the related articles beginning on pages 2105 and 2094, respectively). Strikingly, both groups report an important contribution by macrophages, implying that macrophages can contribute to both epithelial-based and T cell-mediated pathways of inflammation.

Figure 1. An emerging model of psoriasis pathogenesis in humans.

Many insults can lead to the activation of dermal dendritic cells, a key initiating step in the development of psoriasis in predisposed individuals. Activated dendritic cells induce the proliferation of autoreactive T cells within the dermis, inducing production of IFN-γ and TNF-α, which in turn induces the production of MCP-1 and other chemotactic cytokines by epidermal cells. These chemotactic agents induce influx of monocytes from the blood, which undergo differentiation into macrophages and myeloid dendritic cells. The studies of Stratis et al. (12) and Wang et al. (20) reported in this issue of the JCI suggest that these dermal macrophages, once activated by T cell or dendritic cell cytokines, then produce large amounts of TNF-α, leading to the skin changes observed in psoriasis. PRR, pathogen-recognition receptor.