Cross-Disease Transcriptomics: Unique IL-17A Signaling in Psoriasis Lesions and an Autoimmune PBMC Signature

Abstract

Transcriptome studies of psoriasis have identified robust changes in mRNA expression through large-scale analysis of patient cohorts. These studies, however, have analyzed all mRNA changes in aggregate, without distinguishing between disease-specific and non-specific differentially expressed genes (DEGs). In this study, RNA-seq meta-analysis was used to identify (1) psoriasis-specific DEGs altered in few diseases besides psoriasis and (2) non-specific DEGs similarly altered in many other skin conditions. We show that few cutaneous DEGs are psoriasis-specific and that the two DEG classes differ in their cell type and cytokine associations. Psoriasis-specific DEGs are expressed by keratinocytes and induced by IL-17A, whereas non-specific DEGs are expressed by inflammatory cells and induced by IFN-gamma and TNF. PBMC-derived DEGs were more psoriasis-specific than cutaneous DEGs. Nonetheless, PBMC DEGs associated with MHC class I and NK cells were commonly downregulated in psoriasis and other autoimmune diseases (e.g., multiple sclerosis, sarcoidosis and juvenile rheumatoid arthritis). These findings demonstrate “cross-disease” transcriptomics as an approach to gain insights into the cutaneous and non-cutaneous psoriasis transcriptomes. This highlighted unique contributions of IL-17A to the cytokine network and uncovered a blood-based gene signature that links psoriasis to other diseases of autoimmunity.

IL-17 Signaling Triggers Degradation of the Constitutive NF-κB Inhibitor ABIN-1

“…Exacerbated IL-17R signaling is associated with psoriasis and other autoimmune conditions (2,(26)(27)(28). Accordingly, it is not surprising that there are negative regulators that act on the IL-17 signaling cascade to prevent the overexuberant inflammatory responses that underlie tissue pathology.…”

645 Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis

“…Gene expression in human psoriasis was evaluated using results from an RNA-seq meta-analysis comparing gene expression in psoriasis lesions to uninvolved skin from 44 patients (Gene Expression Omnibus (GEO) series identifiers GSE41745, GSE54456/GSE63979, GSE66511) [45]. Additional datasets incorporated into analyses include those from prior microarray studies of IMQ dermatitis in mice (GSE27628, GSE47607, GSE60804, GSE63684, GSE78057) [2,[20][21][22], human KCs treated with poly(I:C) (GSE21260) [46], human KCs treated with IL-17A (GSE12109, GSE24767, GSE27533, GSE32620, GSE36287, GSE52361, GSE53751), the Immunological Genome Project (IGP; GSE15907) [47,48], macroscopically normal human skin from control subjects without skin disease (n = 90 subjects; GSE54456; Additional file 2), laser capture microdissected human suprabasal and basal epidermis (GSE42114) [49], regenerated human epidermis organotypic cultures (GSE52953) [50], Mediterranean spotted fever eschars (GSE32993), burn wound margins 0-3 days post-injury (GSE8056) [51], and Leishmania braziliensis-infected cutaneous lesions (GSE55664) [52].…”

“…Additional datasets incorporated into analyses include those from prior microarray studies of IMQ dermatitis in mice (GSE27628, GSE47607, GSE60804, GSE63684, GSE78057) [2,[20][21][22], human KCs treated with poly(I:C) (GSE21260) [46], human KCs treated with IL-17A (GSE12109, GSE24767, GSE27533, GSE32620, GSE36287, GSE52361, GSE53751), the Immunological Genome Project (IGP; GSE15907) [47,48], macroscopically normal human skin from control subjects without skin disease (n = 90 subjects; GSE54456; Additional file 2), laser capture microdissected human suprabasal and basal epidermis (GSE42114) [49], regenerated human epidermis organotypic cultures (GSE52953) [50], Mediterranean spotted fever eschars (GSE32993), burn wound margins 0-3 days post-injury (GSE8056) [51], and Leishmania braziliensis-infected cutaneous lesions (GSE55664) [52]. Comparisons to 35 human skin diseases were made using a database of 124 expression signatures compiled and described in a previous publication [45]. IGP data were processed and analyzed to identify cell type-specific genes as described previously [47].…”

“…Genes altered by IMQ overlap significantly with those altered in other human skin conditions besides psoriasis (wounding, acne, eschars, infection) Gene expression patterns in psoriasis overlap considerably with those in other human skin diseases [45]. We therefore considered whether expression responses to IMQ in mice were consistent with other human skin diseases besides psoriasis (Fig.…”

Medicinal Plants to Calm and Treat Psoriasis Disease

“…Among the types of the mentioned skin diseases, psoriasis and eczema (such as seborrhoeic eczema) can be one of the varieties of autoimmune diseases that environmental factors intensify their symptoms [2][3][4][5][6][7]. Also, these diseases, especially psoriasis, are so important, throughout the world due to the direct impact on quality of life.…”