Trained immunity in the inflammatory cascade of chronic inflammatory skin diseases: possible checkpoints and new therapeutic targets

Chronic inflammatory skin diseases—such as atopic dermatitis, psoriasis (PSO), and hidradenitis suppurativa—result from epidermal barrier defects combined with dysregulated immune responses, producing lesions that range from eczematous changes to hyperproliferative plaques. Increasing evidence implicates the innate immune system, and specifically “trained immunity,” in sustaining chronic cutaneous inflammation (1-4). Trained immunity refers to long-lasting functional, metabolic, and epigenetic reprogramming of myeloid cells that amplifies inflammatory responses after secondary challenges (5). Key mechanisms include mTOR-dependent metabolic shifts, notably enhanced aerobic glycolysis and histone modifications that potentiate cytokine production (6). Monocytes from patients with systemic immune disorders, such as rheumatoid arthritis (RA) and systemic lupus erythematosus, exhibit trained-immunity features, suggesting a broader pathogenic role beyond classical adaptive immunity. Given shared inflammatory pathways between RA and PSO/psoriatic arthritis, and the documented involvement of mTOR signaling in skin inflammation, investigating trained immunity in dermatologic diseases is warranted (7). Additionally, chronic graft-versus-host disease (cGVHD), a common posttransplant complication with dominant skin manifestations driven by Th1/Th17 hyperinflammation, similarly engages trained-immunity pathways (8). Because human skin and its microbiota continuously emit volatile and semi-volatile organic compounds that reflect metabolic states, two-dimensional gas chromatography coupled to mass spectrometry (GC×GC-TOFMS) was exploited to quantify these emissions from human samples and identify metabolic and volatile biomarkers associated with trained immunity (9). The study aims to characterize trained immunity mechanisms directly in paediatric and adult populations and to identify early-onset pathways and metabolic checkpoints for future precision medicine approaches. Our activity was particularly dedicated to paediatric population analyses.