Chaudhary Rishabh, Azam Mohd Akhtar, Dowand Bhavana, Singh Alpana, Rehman Mujeeba, Agarwal Vipul, Kumar Anand, Kaushik Arjun Singh, Srivastava Sukriti, Srivastava Siddhi, Mishra Vikas
Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, 226025, U.P., India.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr;398(4):4305-4334. doi: 10.1007/s00210-024-03529-2. Epub 2024 Oct 25.
Chronic stress is significantly implicated in the worsening of autoimmune disorders, contributing to elevated inflammation and diminished therapeutic efficacy. Here, in this study, we investigated the detrimental impact of an 8-week chronic unpredictable stress (CUS) protocol on the progression of arthritis and psoriasis using collagen-induced arthritis (CIA) and imiquimod (IMQ)-induced psoriasis rat models, respectively. Our objective was to elucidate how prolonged stress exacerbates disease severity and impairs the effectiveness of treatment drug. Following the induction of CIA and IMQ, rats were subjected to an 8-week CUS paradigm designed to simulate chronic stress conditions. Moreover, after 5 weeks of CUS, methotrexate (MTX; 2 mg/kg, administered once weekly for 3 weeks, intraperitoneally) was introduced as a therapeutic intervention. The severity of CUS-induced effects and the therapeutic impairment of MTX in arthritis and psoriasis rats were assessed through pathological examination of joint and epidermal tissues, respectively. Additionally, we measured various pro-inflammatory cytokine levels, including NF-κB (nuclear factor kappa B), IFN-γ (interferon-gamma), TNF-α (tumour necrosis factor alpha), IL (interleukin)-1β, IL-6, IL-17 and IL-23 using enzyme-linked immunosorbent assay (ELISA), analysed immune cells through complete haematological profiling and evaluated oxidative stress markers. Our findings revealed that CUS significantly aggravated the pathological features of both arthritis and psoriasis. Prolonged stress exposure led to heightened inflammatory responses, increased oxidative stress and more severe tissue damage. Moreover, the therapeutic efficacy of MTX was notably reduced in stressed rats compared to non-stressed, underscoring the detrimental effects of chronic stress on treatment outcomes. Taken together, our results emphasize the importance of considering chronic stress as a critical factor in the management of autoimmune diseases.
慢性应激与自身免疫性疾病的恶化密切相关，会导致炎症加剧和治疗效果降低。在此项研究中，我们分别使用胶原诱导性关节炎（CIA）和咪喹莫特（IMQ）诱导的银屑病大鼠模型，研究了为期8周的慢性不可预测应激（CUS）方案对关节炎和银屑病进展的有害影响。我们的目的是阐明长期应激如何加剧疾病严重程度并损害治疗药物的有效性。在诱导CIA和IMQ后，大鼠接受为期8周的CUS范式，以模拟慢性应激条件。此外，在CUS 5周后，引入甲氨蝶呤（MTX；2 mg/kg，每周腹腔注射1次，共3周）作为治疗干预。通过对关节和表皮组织进行病理检查，分别评估CUS诱导的效应的严重程度以及MTX对关节炎和银屑病大鼠的治疗损害。此外，我们使用酶联免疫吸附测定（ELISA）测量了各种促炎细胞因子水平，包括核因子κB（NF-κB）、干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β、IL-6、IL-17和IL-23，通过全血细胞分析分析免疫细胞，并评估氧化应激标志物。我们的研究结果表明，CUS显著加重了关节炎和银屑病的病理特征。长期应激暴露导致炎症反应增强、氧化应激增加和更严重的组织损伤。此外，与未应激的大鼠相比，应激大鼠中MTX的治疗效果明显降低，这突出了慢性应激对治疗结果的有害影响。综上所述，我们的结果强调了将慢性应激视为自身免疫性疾病管理中的关键因素的重要性。
