The IL-36 Cytokine Rheostat: Hierarchical Regulation of Epithelial-Immune Crosstalk and Precision Therapy in...

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.