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.

Pellino‐1 expression is associated with epidermal proliferation and enhanced Th17 cell infiltration in psoriatic lesions

“…6,[20][21][22] We previously reported, based on a mouse model, that Pellino-1 overexpression induces keratinocyte proliferation in the S and G2/M phases of the cell cycle, chronic skin inflammation and an increase in several Th17-related cytokines, causing psoriasis-like skin lesions. 11 Consistent with these previous findings, we show here that Pellino-1 expression is also increased in human patients with psoriasis and is related to disease activity and T helper cell infiltration. Interestingly, these changes in Pellino-1 expression observed in our present analyses were mainly found in the epidermis, the predominantly affected region in psoriasis, but not in the dermis or subcutis.…”

“…In recent studies, single-cell RNA sequencing of relapsing psoriatic lesions revealed the high enrichment of gene signatures indicative of Th17 cells and the PELI1 gene, indicating that Pellino-1 activates Th17 cell immune responses. 11,25 Furthermore, we also validated the association between epidermal Pellino-1 expression and CD4 + Pellino1 + RORγt + T cell infiltration into the skin lesions of psoriasis patients. The pivotal role of Th17 cells has been reported in the pathogenesis of immune-mediated inflammatory diseases, such as periodontitis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, Sjögren syndrome, Type 1 diabetes mellitus and axial spondylitis, as well as psoriatic arthritis and psoriasis.…”

“…Pellino‐1, a ubiquitin E3 ligase, promotes B, T and epithelial cell proliferation and regulates innate pattern‐recognition receptor signalling and innate immune responses 8–12 . Moreover, it activates Toll‐like receptor and T cell receptor signalling‐mediated proinflammatory gene expression.…”

“…2,7 Pellino-1, a ubiquitin E3 ligase, promotes B, T and epithelial cell proliferation and regulates innate pattern-recognition receptor signalling and innate immune responses. [8][9][10][11][12] Moreover, it activates Toll-like receptor and T cell receptor signalling-mediated proinflammatory gene expression. Recently, it has been reported that Pellino-1 is increased in chronic inflammatory immune diseases and hematolymphoid malignancies, such as neutrophilic asthma, systemic lupus erythematosus, inflammatory lung diseases and diffuse large B-cell lymphoma.…”

The role of interleukin-24 in atopic dermatitis

“…Pellino 1 ubiquitin E3 ligase is activated by innate pattern-recognition receptors such as Toll-like receptors. Overexpression of Pellino 1 induced a significant increase in the expression of IL-24 in HaCaT cells [29].…”