Melatonin inhibits salivary gland epithelial cell ferroptosis via the NRF2/HO-1/GPX4 signaling pathway in primary Sjögren's syndrome.

IF 4.8 3区 医学 Q2 CELL BIOLOGY
Xiuhong Weng, Simin Wang, Qing Wang, Mingbo Wei, Bo Cheng
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Abstract

Background: Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by xerostomia and autoimmune sialadenitis. Interferon-γ (IFN-γ) induces ferroptosis in salivary gland epithelial cells (SGECs), leading to salivary gland (SG) hypofunction. We previously demonstrated the beneficial effects of melatonin (MLT) in alleviating SG dysfunction and inflammation in a pSS animal model. However, the precise underlying mechanism remains unclear.

Methods: Female NOD/ltj and ICR mice were used as the pSS mouse model and control group, respectively. MLT was administered via intraperitoneal injection to NOD/ltj mice to detect its effect on ferroptosis in SGs. Primary human SGECs and A253 cells were treated with IFN-γand ferroptosis inducers, with or without MLT.

Results: Exogenous MLT alleviated pathological SG alterations and promoted saliva production through inhibiting SGEC ferroptosis. MLT inhibited SGEC ferroptosis induced by IFN-γ and ferroptosis inducers via nuclear factor erythroid 2-related factor 2/heme oxygenase-1/glutathione peroxidase 4 (NRF2/HO-1/GPX4) pathway activation. Moreover, MLT suppressed the nuclear factor-kappa B (NF-κB) pathway, which is triggered by ferroptosis in SGECs. Nevertheless, ML385-mediated NRF2 inhibition abrogated the antiferroptotic protective effects of MLT on SGECs.

Conclusions: MLT inhibits SGEC ferroptosis through NRF2/HO-1/GPX4 pathway activation and thus attenuates ferroptosis-triggered NF-κB activity. Melatonin represents a potential therapeutic approach for pSS owing to its capacity to regulate ferroptosis.

褪黑素通过NRF2/HO-1/GPX4信号通路抑制原发性Sjögren综合征唾液腺上皮细胞铁下垂。
背景:原发性Sjögren综合征(pSS)是一种以口干和自身免疫性涎腺炎为特征的自身免疫性疾病。干扰素-γ (IFN-γ)诱导唾液腺上皮细胞(SGECs)铁下垂,导致唾液腺(SG)功能减退。我们之前在pSS动物模型中证明了褪黑素(MLT)在缓解SG功能障碍和炎症方面的有益作用。然而,确切的潜在机制仍不清楚。方法:将NOD/ltj雌性小鼠和ICR雌性小鼠分别作为pSS小鼠模型和对照组。以NOD/ltj小鼠腹腔注射MLT,观察其对SGs大鼠铁下垂的影响。用IFN-γ和铁下垂诱导剂处理原代人SGECs和A253细胞,并在有或没有MLT的情况下处理。结果:外源性MLT通过抑制SGEC铁下垂减轻病理性SG改变,促进唾液分泌。MLT通过激活NRF2/HO-1/GPX4通路抑制IFN-γ和铁衰亡诱导剂诱导的SGEC铁衰亡。此外,MLT抑制核因子κB (NF-κB)通路,这是由sges铁下垂引发的。然而,ml385介导的NRF2抑制消除了MLT对sges的抗铁衰保护作用。结论:MLT通过激活NRF2/HO-1/GPX4通路抑制SGEC铁下垂,从而减弱铁下垂引发的NF-κB活性。褪黑素由于其调节铁下垂的能力,代表了pSS的潜在治疗方法。
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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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