T cells and cytokines in inflamed psoriatic skin. Who's in charge?

Summary

Inflammation in psoriasis is driven through the IL‐23/IL‐17 pathway. Monoclonal antibodies targeting cytokines in the pathway have proven highly effective and are widely used in clinical practice. There is still much to learn, however, about how these pathogenic responses are controlled, particularly with respect to the highly immunologically active molecules produced by the inflamed skin tissue itself. These tissue‐derived molecules, which include IL‐33, play important roles in modulating chronic inflammation that we are only beginning to understand. Here we highlight new research indicating a role for IL‐33 in modulating the inflammatory Th17 response in psoriasis, which may provide avenues for developing new psoriasis treatments.

Psoriasis is a chronic inflammatory disorder affecting the skin, associated in some patients with joint inflammation and an increased incidence of obesity, heart disease, diabetes, stroke, and autoimmune conditions. ¹ Its pathogenesis is known to involve pro‐inflammatory cytokines including TNFα, IL‐17 and IL‐23. This cytokine profile indicated the likely involvement of IL‐17‐producing γδ and αβ T cells (Th17 cells) and other IL‐17 producing cells in disease pathogenesis. ² , ³ Indeed, monoclonal antibodies specific for IL‐12/IL‐23p19, IL‐23p40, TNF, and IL‐17A are highly effective and established therapies for the treatment of severe psoriasis. ⁴ , ⁵ These agents have revolutionised psoriasis treatment, but both the potential for serious side effects and the loss of effectiveness over time drive the search for a deeper understanding of disease pathogenesis to help identify novel therapeutic approaches.

In order to generate this deeper understanding of how pathogenic Th17 responses are controlled in psoriasis, it is important to consider the local cytokines in inflamed skin that may contribute to or regulate the inflammatory response. Prominent among these is IL‐33, a pleiotropic cytokine produced in response to damage by endothelial and epithelial cells, including keratinocytes in inflamed human skin. IL‐33 acts by signalling through its ligand, ST2, and is thus able to drive proliferation and Th2 cytokine production both directly by ST2‐expressing Th2, ILC2 and Treg cells, and indirectly by stimulating Th2 cells via ST2‐expressing dendritic and mast cells. ⁶ In psoriatic skin samples these mast cells frequently also express IL‐6, and may therefore contribute to Th17 or Treg maintenance. ⁷ Thus, although IL‐33 expression has been observed in psoriatic skin tissue, ⁸ its contributions to the pathogenic Th17 response in psoriasis is currently unclear.

Mouse models of inflammation can be powerful tools to investigate potential immunological mechanisms underlying pathology, especially if used to answer carefully framed questions and compared with relevant data from patients. In this issue, we report a study that describes how, in both a mouse model of psoriatic inflammation and in people with psoriasis, IL‐33 may contribute to reducing skin inflammation by acting directly on Th17 cells. ⁹ The authors initially demonstrate that patients with psoriasis have relatively higher levels of cutaneous and circulating IL‐33 than a control cohort, and that addition of IL‐33 to patients’ CD4 T cells in vitro reduces the frequency of IL‐17A‐expressing cells. To investigate the mechanisms by which this IL‐33 may influence inflammation in vivo, they initiate skin inflammation in mice by topical application of the TLR7/8 agonist imiquimod, and inject IL‐33 subcutaneously. This IL‐33 injection reduces the induced cutaneous inflammation, with reduced infiltration of T cells into the skin; reduced levels of cutaneous and systemic inflammatory cytokines; and reduced proportions of Th17 cells in the skin‐draining lymph nodes of the imiquimod‐treated mice.

The fact that IL‐33 is able to inhibit skin inflammation in this model is interesting, and is consistent with the idea that IL‐33 may inhibit Th17 cell functions. Questions still remain, however, about the mechanisms by which IL‐33 may inhibit this inflammation. It could be a direct effect or, as the authors discuss, perhaps an indirect effect operating through Tregs, or iNKT cells. Questions also remain about whether this may be a useful therapeutic strategy, as the patients with psoriasis in this study had increased lesional and circulating IL‐33, and a previous report has demonstrated that IL‐33 is able to exacerbate skin inflammation. ¹⁰ In order to resolve these issues, it will be important to pay close attention to the contributions made by IL‐33 and the other highly active immunomodulatory compounds produced by damaged skin tissue. These tissue‐derived compounds, and their complex interactions with chronically activated immune cells, may provide clues to developing productive novel strategies for treating psoriasis.