Cytokine Dynamics in Inflammatory Skin Diseases

Cytokine networks within the skin govern the initiation, amplification and resolution of inflammation. In inflammatory dermatoses such as plaque psoriasis and pustular variants, dysregulated production of interleukins by keratinocytes, immune cells and structural epidermal elements establishes self-sustaining circuits. Central to this process are interleukin-36 cytokines, which upon proteolytic maturation act on keratinocytes and myeloid cells to induce pro-inflammatory gene programmes and recruit neutrophils. Parallel activation of T helper 17 pathways via interleukin-17A further exacerbates epidermal proliferation and sustains a feed-forward loop with IL-36 agonists, driving chronic plaque formation. Recent insights have highlighted neutrophil-derived interleukin-26 as a pivotal autoinflammatory mediator, linking innate immune activation with keratinocyte dysfunction through Toll-like receptor engagement. Genetic variants affecting IL36RN, CARD14 and autophagy pathways within keratinocytes underscore the contribution of intrinsic epidermal defects to cytokine hyperactivation. Collectively, these findings reveal a complex interplay between innate and adaptive arms of immunity at the skin interface, offering mechanistic rationale for targeted intervention and emphasising the need for therapies that restore cytokine equilibrium and barrier homeostasis.

Research from Nature Portfolio

Recent studies have shown that interleukin-17A and IL-36 cytokines act in concert to regulate keratinocyte differentiation and barrier function. Work using three-dimensional skin models demonstrated that IL-17A represses key differentiation markers while inducing the expression of inactive IL-36α, IL-36β and IL-36γ, which require neutrophil-derived proteases for activation. Once processed, these IL-36 agonists synergise with IL-17A to amplify inflammatory gene programmes, reinforcing an epidermal amplification loop implicated in persistent psoriatic lesions. This mechanistic synergy provides a conceptual framework for dual targeting of TH17 and IL-36 pathways in chronic plaque psoriasis.

Cytokine Dynamics in Inflammatory Skin Diseases publication trend

The graph below shows the total number of articles in cytokine dynamics in inflammatory skin diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Cytokine: A soluble protein secreted by cells that mediates intercellular communication in immune responses.

Keratinocyte: The predominant epidermal cell type responsible for barrier formation and cytokine production in skin.

Neutrophil: A short-lived innate immune cell that releases granule contents and cytokines during inflammation.

Autoinflammation: Sterile inflammation driven by innate immune dysregulation without high-titer autoantibodies.

Interleukin-36 (IL-36): A subfamily of IL-1 cytokines requiring proteolytic processing to exert pro-inflammatory effects in skin.

Interleukin-17A (IL-17A): A T helper 17 cytokine that promotes keratinocyte activation and synergises with IL-36 in psoriatic inflammation.

Proteolytic activation: Enzymatic cleavage of precursor proteins to generate biologically active cytokines.

Autophagy: A cellular recycling process that regulates protein turnover and can modulate inflammatory signalling.

References

1. Autoinflammatory Keratinization Diseases—The Concept, Pathophysiology, and Clinical Implications. Clinical Reviews in Allergy & Immunology (2023).
2. Human neutrophils drive skin autoinflammation by releasing interleukin (IL)-26. Journal of Experimental Medicine (2024).
3. Interleukin-36 (IL-36) Ligands Require Processing for Full Agonist (IL-36α, IL-36β, and IL-36γ) or Antagonist (IL-36Ra) Activity. Journal of Biological Chemistry (2011).
4. AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production. Journal of Investigative Dermatology (2016).
5. The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function. Scientific Reports (2017).