Pellino 1 Communicates Intercellular Signaling in Chronic Skin Inflammatory Microenvironment

Abstract

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 signalresponsive 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 psoriasis. In summary, Peli1-mediated ubiquitination is a common immunopathogenic intercellular signaling in psoriasis-like chronic skin inflammatory microenvironment. Thus, targeting Peli1 could be used as a potential strategy for psoriasis treatment.

Immune Control by TRAF6-Mediated Pathways of Epithelial Cells in the EIME (Epithelial Immune Microenvironment)

“…Peli1 promotes microglial TRAF6-mediated MAPK activation in EAE (114). Specifically, Peli1 mediates TRAF6-induced K63-linked polyubiquitination of c-IAP [c-inhibitor of apoptosis protein: a member of other E3 ubiquitin ligase family IAP (115)], which then ubiquitinates TRAF3 with K48 linkage, resulting in TRAF3 degradation and thereby removing its suppression of the signaling for MAPK activation (Figure 6). Blockade of IRAK1–Peli1–TRAF6 signaling by TGF-β-mediated Smad6–Peli1 interaction is involved in the anti-inflammatory effects of TGF-β signaling (116).…”

“…Moreover, Peli1 is possibly involved in the development of psoriasis. Peli1 expression is enhanced in the epidermis of psoriasis lesions, and doxy-inducible Peli1 tg mice spontaneously develop psoriatic inflammation, which depends on Peli1 overexpression in radioresistant cells, with increased expression levels of IL-17 and IL-22 in the skin (115). In addition, imiquimod-induced psoriatic dermatitis is impaired in Peli1 deficient mice.…”

“…These results suggest possible regulatory roles of Peli1 in IL-17 signaling in epithelial cells. In these mice, however, the involvement of Peli1 in keratinocyte-specific TRAF6 signaling remains unexplored (115).…”