Psoriasis: A STAT3-Centric View

Abstract

Signal Transducer and Activator of Transcription (STAT)3 has recently emerged as a key player in the development and pathogenesis of psoriasis and psoriatic-like inflammatory conditions. Indeed, STAT3 hyperactivation has been reported in virtually every cell type involved in disease initiation and maintenance, and this factor mediates the signal of most cytokines that are involved in disease pathogenesis, including the central Interleukin (IL)-23/IL-17/IL-22 axis. Despite the recent availability of effective biological agents (monoclonal antibodies) against IL-17 and IL-23, which have radically changed the current standard of disease management, the possibility of targeting either STAT3 itself or, even better, the family of upstream activators Janus kinases (JAK1, 2, 3, and TYK2) offers additional therapeutic options. Due to the oral/topical administration modality of these small molecule drugs, their lower cost, and the reduced risk of eliciting adverse immune responses, these compounds are being actively scrutinized in clinical settings. Here, we summarize the main pathological features of psoriatic conditions that provide the rationale for targeting the JAK/STAT3 axis in disease treatment.

Keywords: Janus kinases; STAT3; Th17 cells; autoimmunity; psoriasis; skin inflammation.

Figure 1

The scheme depicts the main cell types involved in psoriasis pathogenesis, the cytokines/chemokines produced and their target cells. The arrows indicate cytokines that are produced by the different cell types, and the cells where these mainly exert their effector functions. The yellow stars represent events of cytokine-induced STAT3 activation. In the blow-ups, indicated by the dotted lines, the two main cell types involved, Th17 CD4⁺ T lymphocytes, and keratinocytes, along with details of STAT3-mediated functions and a description of their main pathogenetic features are represented. See text for details and references.