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

Suhyeon Kim,Si-Yeon Lee,Seoyoon Bae,Chang-Woo Lee,Jin-Kwan Lee,Heounjeong Go,Kyungrim Hwang

doi:10.1038/s12276-020-00489-4

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.

Highlights

The development of psoriasis requires cross-talk between innate immunity and adaptive immune responses
We found significant changes in the expression levels of several T helper 17 (Th17)-related cytokines, such as those secreted by Th17 cells (IL-17a, IL-21, IL-22, and IL-24), cytokines involved in Th17 differentiation (IL-21 and IL-23), and the chemokine CCL20 involved in the trafficking of Th17 cells
Overexpression of Peli[1] in keratinocytes induces upregulation of IL-21 and IL-24, activation of STAT3 signaling, and the secretion of mediators underlying the differentiation of Th17 and Th1 cells

Summary

Introduction

The development of psoriasis requires cross-talk between innate immunity and adaptive immune responses. Dysregulation of the skin inflammatory signaling pathway results in keratinocyte hyperproliferation and is one of the key pathogenic mechanisms underlying the development of psoriasis[1]. Both αβ and γδ T cells synthesize IL-17, while activated Dendritic cells (DCs) secrete IL-23 and IL-12. They stimulate three populations of resident T cells: Th17, Th22, and Th1 cells[2,3]. IL-23 activates Th17 cells to release IL-17A and IL-17F, which induce keratinocyte hyperactivation. T cell-derived and DC-derived cytokines act on epidermal keratinocytes as proximal inducers of immunogenic circuits in psoriasis. Skin epidermal cells release an abundance of cytokines, chemokines, and other inflammatory mediators, including CXCL8, monocyte chemotactic protein-1/CCL2, CXCL13, and CCL205–7. Selective activation of immune cells alone is not sufficient for the initiation of psoriasis

Methods

Results

Conclusion