Pellino 1 Communicates Intercellular Signaling in Chronic Skin Inflammatory Microenvironment

Chronic skin inflammation including psoriasis is a multisystem disease, affecting more than 5% of the general population. Here we show that Pellino 1 (Peli1), a signal-responsive ubiquitin E3 ligase, is highly up-regulated in human psoriatic skin lesions and that increased Peli1 expression correlates with the immunopathogenesis of psoriasis-like chronic skin inflammatory disease. Interestingly, Peli1 directly interacts with interferon regulatory factor 4 (IRF4, a transcription factor that plays pivotal roles in proliferation and cytokine production) and induces lysine 63-mediated ubiquitination. Peli1-mediated IRF4 ubiquitination appears to be a common systemic signaling mechanism shared by lesional keratinocytes, dendritic cells, macrophages, and T cells, generating a feedback relationship between keratinocyte and Th17 cell responses. Conversely, inhibition of Peli1 interferes with IRF4 induction and attenuates immunopathogenic signaling in the psoriatic microenvironment. In summary, Peli1-mediated ubiquitination is a common immunopathogenic intercellular signaling in psoriasis-like chronic skin inflammatory disease. Thus, targeting Peli1 could be used as a potential strategy for psoriasis treatment.