Abstract
Interleukin (IL)-1 family cytokines initiate inflammatory responses, and shape innate and adaptive immunity. They play important roles in host defense, but excessive immune activation can also lead to the development of chronic inflammatory diseases. Dysregulated IL-1 family signaling is observed in a variety of skin disorders. In particular, IL-1 family cytokines have been linked to the pathogenesis of psoriasis and atopic dermatitis. The biological activity of pro-inflammatory IL-1 family agonists is controlled by the natural receptor antagonists IL-1Ra and IL-36Ra, as well as by the regulatory cytokines IL-37 and IL-38. These four anti-inflammatory IL-1 family members are constitutively and highly expressed at steady state in the epidermis, where keratinocytes are a major producing cell type. In this review, we provide an overview of the current knowledge concerning their regulatory roles in skin biology and inflammation and their therapeutic potential in human inflammatory skin diseases. We further highlight some common misunderstandings and less well-known observations, which persist in the field despite recent extensive interest for these cytokines.
Highlights
The biological activity of pro-inflammatory IL-1 family cytokines is controlled at the level of their production and maturation, as well as by natural receptor antagonists and regulators belonging to the IL-1 cytokine family, and by decoy or inhibitory receptors belonging to the IL-1 receptor family
This review summarizes recent advances in the understanding of the biology of antiinflammatory members of the IL-1 cytokine family, IL-1 receptor (IL-1R) antagonist (IL-1Ra), IL-36Ra, IL-37 and IL-38, and of their role in the control of inflammatory responses in human and mouse skin
In a mouse model for this pathology, Anakinra administration reduced neutrophilic infiltrates in the skin [190]. These findings demonstrate an anti-inflammatory role of IL-1Ra in mouse models of skin inflammation
Summary
In the mouse Aldara (5% IMQ) model, IL-36 signaling in keratinocytes is crucial for disease initiation by mediating the recruitment of neutrophils [24, 79], and controlling the expression of IL-23 at early time points [79]. Some studies reported intracellular roles for icIL-1Ra1 in vitro in modulating inflammatory responses, cell proliferation or differentiation in different cell types, including keratinocytes [33, 34, 107,108,109], but others could not confirm intracellular effects [32, 94, 105, 110].
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