ReviewClinical, cosmetic and investigational dermatology2026
The IL-36 Cytokine Rheostat: Hierarchical Regulation of Epithelial-Immune Crosstalk and Precision Therapy in Psoriatic and Related Dermatoses.
Review in Clinical, cosmetic and investigational dermatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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7 authors.
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Abstract
The interleukin-36 (IL-36) cytokine subfamily-comprising IL-36α, IL-36β, IL-36γ, and their natural antagonists IL-36Ra and IL-38-has emerged as a central regulator of epithelial-immune communication and systemic inflammation. Acting through the IL-36 receptor complex (IL-1Rrp2/IL-1RAcP), IL-36 can be conceptualized as integrating protease-dependent molecular activation, multicellular amplification loops, and disease-specific network crosstalk within a unified hierarchical framework. At the molecular level, neutrophil-derived proteases license IL-36 activation, establishing a threshold that converts barrier stress into inflammatory signaling. Within cellular networks, keratinocyte-derived IL-36γ amplifies dendritic cell-Th17 interactions and neutrophil recruitment, while the antagonists IL-36Ra and IL-38 provide feedback restraint. Across the psoriatic spectrum, IL-36 acts as a driver cytokine in generalized pustular psoriasis (GPP), an amplifier in plaque psoriasis (PV), and a sustainer in psoriatic arthritis (PsA)-defining a gradient of cytokine dependency that is conceptually consistent with differential therapeutic responsiveness. Beyond psoriasis, IL-36 participates in neutrophilic, fibrosing, and atopic dermatoses, serving as a convergent inflammatory axis that bridges epithelial stress with systemic immune propagation. The successful clinical translation of IL-36R blockade-exemplified by spesolimab and imsidolimab-validates IL-36 as a tractable therapeutic target and underscores its role within the IL-17A/TNF-α/IL-23 cytokine network. Collectively, these advances position IL-36 as a cytokine rheostat capable of scaling immune intensity according to molecular and spatial context. Emerging multi-omic and spatial transcriptomic analyses are now redefining IL-36-high endotypes across inflammatory diseases, suggesting that IL-36 may serve as a reference axis for precision immunotherapy and as a conceptual model for hierarchical immune calibration in chronic inflammation.
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