Department of Internal Medicine and Clinical Immunology, University Hospital of Naples Federico II, Naples, Italy.
Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, Naples, Italy.
Front Immunol. 2024 Sep 6;15:1448560. doi: 10.3389/fimmu.2024.1448560. eCollection 2024.
Neutrophils (polymorphonuclear leukocytes, PMNs) are the most abundant subtype of white blood cells and are among the main actors in the inflammatory response. Psoriatic arthritis (PsA) is a chronic inflammatory disease affecting both the axial and peripheral joints. Typically associated with psoriasis, PsA can also affect multiple systems and organs, including the nails and entheses. Despite the involvement of PMNs in PsA, their specific role in the disease remains poorly understood. This study aimed to characterize the biological functions of PMNs and neutrophil-related mediators in PsA patients.
31 PsA patients and 22 healthy controls (HCs) were prospectively recruited. PMNs were isolated from peripheral blood and subjected to stimulation with lipopolysaccharide (LPS), N-Formylmethionyl-leucyl-phenylalanine (fMLP), tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate (PMA), or control medium. Highly purified peripheral blood PMNs (>99%) were evaluated for activation status, reactive oxygen species (ROS) production, phagocytic activity, granular enzyme and neutrophil extracellular traps (NETs) release. Serum levels of matrix metalloproteinase-9 (MMP-9), myeloperoxidase (MPO), TNF, interleukin 23 (IL-23), and interleukin 17 (IL-17) were measured by ELISA. Serum Citrullinated histone H3 (CitH3) was measured as a NET biomarker.
Activated PMNs from PsA patients displayed reduced activation, decreased ROS production, and impaired phagocytic activity upon stimulation with TNF, compared to HCs. PMNs from PsA patients also displayed reduced granular enzyme (MPO) and NET release. Serum analyses revealed elevated levels of MMP-9, MPO, TNF, IL-23, IL-17, and CitH3 in PsA patients compared to HCs. Serum CitH3 levels positively correlated with MPO and TNF concentrations, and IL-17 concentrations were positively correlated with IL-23 levels in PsA patients. These findings indicate that PMNs from PsA patients show reduced activation and function, and an increased presence of neutrophil-derived mediators (MMP-9, MPO, TNF, IL-23, IL-17, and CitH3) in their serum.
Taken together, our findings suggest that PMNs from PsA patients exhibit an "exhausted" phenotype, highlighting their plasticity and multifaceted roles in PsA pathophysiology.
中性粒细胞（多形核白细胞，PMN）是白细胞中最丰富的亚型，也是炎症反应的主要参与者之一。银屑病关节炎（PsA）是一种影响轴性和外周关节的慢性炎症性疾病。通常与银屑病相关，PsA 还可以影响多个系统和器官，包括指甲和肌腱附着处。尽管 PMN 参与了 PsA，但它们在疾病中的具体作用仍知之甚少。本研究旨在描述 PMN 及其相关介质在 PsA 患者中的生物学功能。
前瞻性招募了 31 名 PsA 患者和 22 名健康对照者（HCs）。从外周血中分离出 PMN，并分别用脂多糖（LPS）、N-甲酰基-甲硫氨酰-苯丙氨酸（fMLP）、肿瘤坏死因子（TNF）、佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）或对照培养基刺激。通过流式细胞术评估高度纯化的外周血 PMN（>99%）的激活状态、活性氧（ROS）产生、吞噬活性、颗粒酶和中性粒细胞胞外陷阱（NETs）释放。通过 ELISA 测定血清基质金属蛋白酶-9（MMP-9）、髓过氧化物酶（MPO）、TNF、白细胞介素 23（IL-23）和白细胞介素 17（IL-17）的水平。用酶联免疫吸附试验（ELISA）测定血清瓜氨酸化组蛋白 H3（CitH3）作为 NET 生物标志物。
与 HCs 相比，来自 PsA 患者的激活 PMN 在受到 TNF 刺激时表现出降低的激活、ROS 产生减少和吞噬活性受损。来自 PsA 患者的 PMN 还表现出颗粒酶（MPO）和 NET 释放减少。与 HCs 相比，PsA 患者的血清中 MMP-9、MPO、TNF、IL-23、IL-17 和 CitH3 水平升高。血清 CitH3 水平与 MPO 和 TNF 浓度呈正相关，而 IL-17 浓度与 PsA 患者的 IL-23 水平呈正相关。这些发现表明，来自 PsA 患者的 PMN 表现出降低的激活和功能，以及其血清中存在增加的中性粒细胞衍生介质（MMP-9、MPO、TNF、IL-23、IL-17 和 CitH3）。
总之，我们的研究结果表明，来自 PsA 患者的 PMN 表现出“耗竭”表型，突出了它们在 PsA 病理生理学中的可塑性和多方面作用。
