G. Barinaga

Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation

Human skin-resident IL-10+ regulatory dendritic cells induce T reg cells that suppress allogeneic skin graft inflammation.

Integrative Biology Approach Identifies Cytokine Targeting Strategies for Psoriasis

The serine/threonine kinase PIM1 is a critical checkpoint for human skin inflammation and potential target in psoriasis. Integrating Autoimmunity True translational biology is a reciprocating process between observations of human disease and clinically relevant animal models. Neither alone is sufficient, but each builds off the other. Perera et al. use such an integrative approach to examine the role of interleukin-22 (IL-22) in psoriasis pathogenesis. The authors found that injecting IL-22 into normal human skin grafts resulted in inflammatory changes that mimicked human psoriasis; these changes could be blocked with an IL-22–neutralizing antibody. They then took this a step further and through transcriptomic and bioinformatic analysis identified hub genes critical for the IL-22/psoriasis connection. One such hub gene, the serine/threonine kinase PIM1, was found to be a critical checkpoint for human skin inflammation and potential future therapeutic target in psoriasis. 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.