The endoribonuclease N4BP1 prevents psoriasis by controlling both keratinocytes proliferation and neutrophil infiltration

Chenliang Gou,Cuihua Lu,Yuanyuan Wu,Panpan Ma,Yu Shen,Zhou Wang,Yingcheng Wu,Renfang Mao,Wenkai Ni,Fengbo Zhao,Yihui Fan,Miaomiao Chen,Rong Sun,Jie Zhang,Hao Chen,Mingbing Xiao

doi:10.1038/s41419-021-03774-w

Abstract

Psoriasis is a common chronic skin disease, characterized by abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells with not fully addressed molecular mechanism. N4BP1 (NEDD4-binding protein 1) is considered as an immune regulator for a long time but its physiological role is not determined yet. Here, we found that the expression of N4BP1 in skin was highest among all 54 tested tissues, and its expression was further upregulated in psoriatic skin. N4BP1-deficient mice exhibited normal grossly, but developed severe and prolonged IMQ-induced psoriasis-like disease comparing to controls. N4BP1 mainly expressed in keratinocytes and located on nucleus. Up- but not downregulated genes in N4BP1-deficient skin were specifically enriched in keratinocyte proliferation and differentiation. The proliferation of N4BP1-deficient primary keratinocytes was faster compared to that of controls. The upregulated genes upon ablation of N4BP1 were highly enriched in targets of AP-1 transcription factor. Knocking out N4BP1 resulted in upregulation of JunB and FosB, and conversely, overexpression of N4BP1 greatly reduced their expression. Furthermore, N4BP1 binds with JunB and FosB encoding mRNAs and greatly reduces their stability. In addition, with a high expression in neutrophils, N4BP1 limits survival of neutrophils in blood and infiltration of neutrophils in psoriatic skin by targeting CXCL1, CCL20, and S100A8. These findings demonstrate that N4BP1 controls the proper function of keratinocytes and neutrophils by negatively regulating JunB, FosB, and CXCL1, respectively, and that is critical for psoriasis prevention.

Highlights

Psoriasis, affecting millions of people worldwide, is chronic localized or systemic skin disease characterized by areas of red, inflamed, itchy, thickened skin, and often covered with silvery scales[1,2]
To systematically assess N4BP1, we explored the expression of N4BP1 using dataset generated through Genotype-Tissue Expression (GTEx) program
The development of psoriasis is a complicated process resulting from abnormal interplay between keratinocytes and immune cells

Summary

Introduction

Psoriasis, affecting millions of people worldwide, is chronic localized or systemic skin disease characterized by areas of red, inflamed, itchy, thickened skin, and often covered with silvery scales[1,2]. Keratinocytes is the major component of the epidermis and its abnormal proliferation and differentiation is the character of psoriasis[9]. Keratinocytes play critical roles throughout the whole pathologic process of psoriasis from initiation, maintenance to relapse[10]. Genetic deletion of JunB and JunC in keratinocytes results in chemokine and cytokine overproduction and sufficiently trigger psoriasis in mice[13,14]. Mice with specific deletion of IKK2 in keratinocytes developed psoriasis-like plaques due to uncontrolled TNFR1 signaling-mediated generation of IL-2415. These studies clearly demonstrate that abnormal keratinocyte might be sufficient to trigger psoriasis even with normal immune cells. The answer might be case-by-case but definitely important to prevent or cure psoriasis in future

Methods

Results

Conclusion