N-acetyltransferase 10 regulates chemokine expression in keratinocytes and promotes atopic dermatitis

IF 9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology Pub Date : 2026-09-17 Epub Date: 2026-07-22 DOI:10.1016/j.chembiol.2026.06.012

Jinjin Shao, Linying Wang, Zhichao Ye, Kexin Wang, Zeren Shen, Ziyi Hong, Ruimin Sun, Lili Zhang, Fang Liu, Siming Zhang, Yunxiang Chen, Zhiqi Xie, Lijiang Zhang

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This study identifies an epitranscriptomic regulatory mechanism in skin immunity by demonstrating that NAT10-mediated RNA cytidine acetylation (ac4C) plays a key role in epithelial-driven inflammation. Rather than operating merely as a generic cellular maintenance factor, NAT10 contributes to the stabilization of specific inflammatory transcripts within barrier-forming keratinocytes, facilitating a pro-inflammatory microenvironment that promotes innate immune cell recruitment. Beyond characterizing this pathway in inflammatory biology, we demonstrate that pharmacological inhibition of this RNA-modifying enzyme mitigates clinical symptoms in preclinical models without apparent systemic toxicity. By connecting chemical RNA modifications to tissue-level immune crosstalk, these findings advance our understanding of tissue homeostasis and provide a conceptual framework for investigating epitranscriptome-targeted strategies in chronic barrier and inflammatory diseases.</div><div><div>Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder with complex immunological underpinnings, yet the role of the RNA acetyltransferase NAT10 in its pathogenesis remains unclear. We investigated NAT10 function through cutaneous NAT10 knockdown (microneedle-delivered AAV-shRNA) and pharmacological inhibition (Remodelin), using 2,4-dinitrochlorobenzene- and ovalbumin-induced murine AD models combined with IFN-γ/TNF-α-stimulated HaCaT keratinocytes. Results showed elevated NAT10 expression and acetylcytidine modification in AD keratinocytes. NAT10 knockdown ameliorated skin pathology, reduced serum IgE, and selectively limited neutrophil infiltration by suppressing chemokines (CXCL8, CCL5, CXCL9, CXCL10, CCL2), whereas its overexpression promoted their expression. Mechanistically, NAT10 stabilized <em>RELB</em> mRNA via acetylcytidine modification, thereby activating NF-κB signaling. Remodelin suppressed keratinocyte chemokine production and neutrophil recruitment, improving skin lesions without toxicity. Collectively, NAT10 emerges as a central regulator of keratinocyte-driven inflammation and a viable therapeutic target in AD.</div></div><div>Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder with complex immunological underpinnings, yet the role of the RNA acetyltransferase NAT10 in its pathogenesis remains unclear. 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引用次数: 0

Abstract

•
NAT10 is upregulated in keratinocytes and drives skin inflammation in AD
•
NAT10-mediated ac4C modification enhances RELB mRNA stability
•
The NAT10/ac4C/RelB axis promotes neutrophil-dominant immune recruitment
•
Pharmacological inhibition of NAT10 by Remodelin alleviates AD pathology

Chronic inflammatory skin disorders, such as atopic dermatitis (AD), affect hundreds of millions of individuals worldwide; yet, the molecular mechanisms bridging epithelial barrier dysfunction and subsequent immune activation remain incompletely understood. This study identifies an epitranscriptomic regulatory mechanism in skin immunity by demonstrating that NAT10-mediated RNA cytidine acetylation (ac4C) plays a key role in epithelial-driven inflammation. Rather than operating merely as a generic cellular maintenance factor, NAT10 contributes to the stabilization of specific inflammatory transcripts within barrier-forming keratinocytes, facilitating a pro-inflammatory microenvironment that promotes innate immune cell recruitment. Beyond characterizing this pathway in inflammatory biology, we demonstrate that pharmacological inhibition of this RNA-modifying enzyme mitigates clinical symptoms in preclinical models without apparent systemic toxicity. By connecting chemical RNA modifications to tissue-level immune crosstalk, these findings advance our understanding of tissue homeostasis and provide a conceptual framework for investigating epitranscriptome-targeted strategies in chronic barrier and inflammatory diseases.

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder with complex immunological underpinnings, yet the role of the RNA acetyltransferase NAT10 in its pathogenesis remains unclear. We investigated NAT10 function through cutaneous NAT10 knockdown (microneedle-delivered AAV-shRNA) and pharmacological inhibition (Remodelin), using 2,4-dinitrochlorobenzene- and ovalbumin-induced murine AD models combined with IFN-γ/TNF-α-stimulated HaCaT keratinocytes. Results showed elevated NAT10 expression and acetylcytidine modification in AD keratinocytes. NAT10 knockdown ameliorated skin pathology, reduced serum IgE, and selectively limited neutrophil infiltration by suppressing chemokines (CXCL8, CCL5, CXCL9, CXCL10, CCL2), whereas its overexpression promoted their expression. Mechanistically, NAT10 stabilized RELB mRNA via acetylcytidine modification, thereby activating NF-κB signaling. Remodelin suppressed keratinocyte chemokine production and neutrophil recruitment, improving skin lesions without toxicity. Collectively, NAT10 emerges as a central regulator of keratinocyte-driven inflammation and a viable therapeutic target in AD.

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n -乙酰转移酶10调节角质形成细胞的趋化因子表达，促进特应性皮炎。

特应性皮炎（AD）是一种慢性复发性炎症性皮肤病，具有复杂的免疫基础，但RNA乙酰转移酶NAT10在其发病机制中的作用尚不清楚。我们使用2,4-二硝基氯苯和卵清蛋白诱导的小鼠AD模型，结合IFN-γ/TNF-α-刺激的HaCaT角质形成细胞，通过皮肤NAT10敲低（微针递送的AAV-shRNA）和药理抑制（重塑蛋白）来研究NAT10的功能。结果显示，AD角质形成细胞中NAT10表达升高，乙酰胞苷修饰。NAT10的下调改善了皮肤病理，降低了血清IgE，并通过抑制趋化因子（CXCL8, CCL5, CXCL9, CXCL10, CCL2）来选择性地限制中性粒细胞浸润，而其过表达则促进了这些趋化因子的表达。机制上，NAT10通过乙酰胞苷修饰稳定RELB mRNA，从而激活NF-κB信号传导。重塑蛋白抑制角化细胞趋化因子的产生和中性粒细胞的募集，改善皮肤病变而无毒性。总的来说，NAT10是角化细胞驱动炎症的中心调节因子，也是AD的可行治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.

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