Intraindividual genome expression analysis reveals a specific molecular signature of psoriasis and eczema

Abstract

Previous attempts to gain insight into the pathogenesis of psoriasis and eczema by comparing their molecular signatures were hampered by the high interindividual variability of those complex diseases. In patients affected by both psoriasis and nonatopic or atopic eczema simultaneously (n = 24), an intraindividual comparison of the molecular signatures of psoriasis and eczema identified genes and signaling pathways regulated in common and exclusive for each disease across all patients. Psoriasis-specific genes were important regulators of glucose and lipid metabolism, epidermal differentiation, as well as immune mediators of T helper 17 (TH17) responses, interleukin-10 (IL-10) family cytokines, and IL-36. Genes in eczema related to epidermal barrier, reduced innate immunity, increased IL-6, and a TH2 signature. Within eczema subtypes, a mutually exclusive regulation of epidermal differentiation genes was observed. Furthermore, only contact eczema was driven by inflammasome activation, apoptosis, and cellular adhesion. On the basis of this comprehensive picture of the pathogenesis of psoriasis and eczema, a disease classifier consisting of NOS2 and CCL27 was created. In an independent cohort of eczema (n = 28) and psoriasis patients (n = 25), respectively, this classifier diagnosed all patients correctly and also identified initially misdiagnosed or clinically undifferentiated patients.

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

“…IL-36 cytokines are overexpressed in affected skin of patients with inflammatory skin diseases, including atopic dermatitis and psoriasis (25)(26)(27)(28). The functional importance of this upregulation is supported by several recent findings: IL-36g mediates the alarmin function of the antimicrobial peptide LL37, and it functions as an alarmin that signals pathogen infections (20,29); injection of IL-36a promotes myeloid cell infiltration and their activation in the skin (30); tg mice overexpressing IL-36a in keratinocytes develop a psoriasis-like phenotype (31); the psoriasiform dermatitis that develops in mice after treatment with imiquimod depends on an IL-36-mediated cross-talk between dendritic cells and keratinocytes (32); and IL-36RA deficiency causes generalized pustular psoriasis in humans (33).…”

NOS2 and CCL27: clinical implications for psoriasis and eczema diagnosis and management

“…Based on our previous findings that patients affected by both psoriasis and eczema at the same time are a unique model to study different inflammatory responses in the same organ [6], we recently performed intraindividual genome expression analysis of biopsy specimens from patients of this rare cohort [7]. In brief, we found that psoriasis-specific genes related to epidermal differentiation, Th17 responses as well as glucose and lipid metabolism, whereas eczema was characterized by genes related to epidermal barrier and Th2-related cytokines.…”

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

“…The expression of IL-36 cytokines is elevated in many inflammatory diseases 22,41 . In particular, high IL-36 as well as mutations in IL-36 signaling components The mean values ± SD of are associated with psoriasis 25,30,[42][43][44][45] . The findings that IL-17A induced the expression of the IL-36 cytokines suggested that these are downstream effectors of IL-17A.…”

“…1 and Supplementary Fig. S1) [16][17][18][19][20]30 . In agreement, we find that IL-17A interferes with differentiation and alters gene expression, which is completely blocked by Secukinumab (Supplementary Fig.…”

“…Members of the IL-36 family, which are IL-1 type cytokines, have also been implicated in psoriasis 22,23 . IL-36 cytokines are involved in the crosstalk between immune cells and keratinocytes and thus are potentially participating in controling the proinflammatory milieu in psoriatic skin [24][25][26][27][28][29][30] . Moreover, interaction of IL-17 and IL-36 has been postulated to promote inflammation 26,31 .…”