Integrative Biology Approach Identifies Cytokine Targeting Strategies for Psoriasis

Abstract

Cytokines are critical checkpoints of inflammation. The treatment of human autoimmune disease has been revolutionized by targeting inflammatory cytokines as key drivers of disease pathogenesis. Despite this, there exist numerous pitfalls when translating preclinical data into the clinic. We developed an integrative biology approach combining human disease transcriptome data sets with clinically relevant in vivo models in an attempt to bridge this translational gap. We chose interleukin-22 (IL-22) as a model cytokine because of its potentially important proinflammatory role in epithelial tissues. Injection of IL-22 into normal human skin grafts produced marked inflammatory skin changes resembling human psoriasis. Injection of anti-IL-22 monoclonal antibody in a human xenotransplant model of psoriasis, developed specifically to test potential therapeutic candidates, efficiently blocked skin inflammation. Bioinformatic analysis integrating both the IL-22 and anti-IL-22 cytokine transcriptomes and mapping them onto a psoriasis disease gene coexpression network identified key cytokine-dependent hub genes. Using knockout mice and small-molecule blockade, we show that one of these hub genes, the so far unexplored serine/threonine kinase PIM1, is a critical checkpoint for human skin inflammation and potential future therapeutic target in psoriasis. Using in silico integration of human data sets and biological models, we were able to identify a new target in the treatment of psoriasis.

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

“…Psoriasis lesion development is closely tied to an underlying cytokine network, which directs and responds to signals from cutaneous cells, including KCs and infiltrating immunocytes (Perera et al, 2014). Previous psoriasis transcriptome studies have highlighted IL-1a, IL-1b, IL-17A and IL-20R1/R2 cytokines (i.e., IL-19, IL-20, IL-24) as in vivo drivers of gene expression in psoriasis lesions (Swindell et al, 2013a; Swindell et al, 2013b; Swindell et al, 2014a; Yao et al, 2008).…”

Integrative RNA-seq and microarray data analysis reveals GC content and gene length biases in the psoriasis transcriptome

“…Gene expression in psoriasis has been extensively studied to generate insights into disease mechanisms, and promising ideas have been advanced for clinical applications based upon expression profiling (48,60). It is likely that RNA-seq will increasingly be the technology of choice for both research and clinical applications, but in agreement with other studies (34), our findings illustrate the complementary nature of these technologies and show how integrative analyses of both data types can be used to distinguish 1) technical trends arising from platform-specific artifacts and 2) nontechnical trends potentially related to the biological processes.…”

The IL-20 subfamily of cytokines — from host defence to tissue homeostasis

“…Second, IL-22 and other IL-20 subfamily members induce the expression of vascular endothelial growth factor A (VEGFA), which is an important growth factor that promotes angiogenesis and neo-vascularization during wound healing 141 . This angiogenesis-promoting effect has been demonstrated for IL-22 in human epidermal cultures 26 , and also in a human skin xenograft model 142 . Third, IL-20 subfamily cytokines promote the reepithelialization process by acting on epidermal keratinocytes.…”