The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins

Abstract

Beyond classic "allergic"/atopic comorbidities, atopic dermatitis (AD) emerges as systemic disease with increased cardiovascular risk. To better define serum inflammatory and cardiovascular risk proteins, we used an OLINK high-throughput proteomic assay to analyze moderate-to-severe AD (n = 59) compared to psoriasis (n = 22) and healthy controls (n = 18). Compared to controls, 10 proteins were increased in serum of both diseases, including Th1 (IFN-γ, CXCL9, TNF-β) and Th17 (CCL20) markers. 48 proteins each were uniquely upregulated in AD and psoriasis. Consistent with skin expression, AD serum showed up-regulation of Th2 (IL-13, CCL17, eotaxin-1/CCL11, CCL13, CCL4, IL-10), Th1 (CXCL10, CXCL11) and Th1/Th17/Th22 (IL-12/IL-23p40) responses. Surprisingly, some markers of atherosclerosis (fractalkine/CX3CL1, CCL8, M-CSF, HGF), T-cell development/activation (CD40L, IL-7, CCL25, IL-2RB, IL-15RA, CD6) and angiogenesis (VEGF-A) were significantly increased only in AD. Multiple inflammatory pathways showed stronger enrichment in AD than psoriasis. Several atherosclerosis mediators in serum (e.g. E-selectin, PI3/elafin, CCL7, IL-16) correlated with SCORAD, but not BMI. Also, AD inflammatory mediators (e.g. MMP12, IL-12/IL-23p40, CXCL9, CCL22, PI3/Elafin) correlated between blood and lesional as well as non-lesional skin. Overall, the AD blood signature was largely different compared to psoriasis, with dysregulation of inflammatory and cardiovascular risk markers, strongly supporting its systemic nature beyond atopic/allergic association.

Figure 1

Regulation of inflammatory and cardiovascular risk proteins in AD and psoriasis vs. healthy controls. Venn diagrams of regulated serum proteins compared to healthy controls, adjusted for age/gender (a) and age/gender/BMI (b). Markers that were significantly upregulated (FCH > 1.3, FDR < 0.1) in both AD and psoriasis (c), only in AD (d) or only in psoriasis (e) are depicted as log2 fold change over healthy control serum with their 95% confidence intervals.

Figure 2

Blood protein correlations with skin disease severity (SCORAD, BSA) and BMI. Pearson correlation coefficients of AD serum proteins significantly correlated with SCORAD (a) and body surface area/BSA (b), and their respective scatter plots (c–j), as well as leptin (k–l), in comparison to correlations with body mass index/BMI.

Figure 3

Blood-skin comparisons. Fold change comparisons of AD serum protein levels (AD vs. healthy controls) and skin MADAD transcriptome levels (lesional vs. non-lesional AD).

Figure 4

Blood-skin correlations of inflammatory mediators. Correlation plots of selected serum protein levels with their corresponding lesional and non-lesional skin mRNA levels (a–j); scatterplots with estimated linear regression and 95% confidence interval; r Pearson correlation; ρ Spearman correlation.

Figure 5

Pathway analysis. Selected pathways enriched in AD and psoriasis serum, compared to respective healthy controls; the green line indicates false discovery rate/FDR < 0.05.