Pellino1 promotes chronic inflammatory skin disease via keratinocyte hyperproliferation and induction of the T helper 17 response

Abstract

Psoriasis is one of the most common immune-mediated chronic inflammatory skin diseases. However, little is known about the molecular mechanism underlying the immunological circuits that maintain innate and adaptive immune responses in established psoriasis. In this study, we found that the Pellino1 (Peli1) ubiquitin E3 ligase is activated by innate pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs), and is highly upregulated in human psoriatic skin lesions and murine psoriasis-like models. Increased Peli1 expression is strongly correlated with the immunopathogenesis of psoriasis by activating hyperproliferation of keratinocytes in the S and G2/M phases of the cell cycle and promoting chronic skin inflammation. Furthermore, Peli1-induced psoriasis-like lesions showed significant changes in the expression levels of several T helper 17 (Th17)-related cytokines, such as IL-17a, IL-21, IL-22, IL-23, and IL-24, indicating that overexpression of Peli1 resulted in the sequential engagement of the Th17 cell response. However, the overexpression of Peli1 in T cells was insufficient to trigger psoriasis, while T cells were indispensable for disease manifestation. In summary, our findings demonstrate that Peli1 is a critical cell cycle activator of innate immunity, which subsequently links Th17 cell immune responses to the psoriatic microenvironment. Psoriasis: Regulatory protein linked to chronic inflammation An immune-regulating protein that mediates chronic inflammation in the skin offers a new therapeutic target for the autoimmune disorder psoriasis. A research team from South Korea led by Chang-Woo Lee from Sungkyunkwan University School of Medicine in Suwon and Heounjeong Go from the University of Ulsan College of Medicine in Seoul have discovered that Pellino1, a protein known to modulate immune responses to pathogens, is also found in abundance in the skin lesions of people with psoriasis. Using mouse models, the researchers showed how Pellino1 induces the proliferation of certain skin cells and triggers an inflammatory state through the activation of small proteins and immune cells normally involved in defense against infection. Targeting strategy that inactivate Pellino1 could help blunt the inflammatory signaling in the skin that drives the development of psoriatic lesions.