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. 2025 Apr;398(4):4305-4334.
doi: 10.1007/s00210-024-03529-2. Epub 2024 Oct 25.

Chronic stress-mediated dysregulations in inflammatory, immune and oxidative circuitry impairs the therapeutic response of methotrexate in experimental autoimmune disease models

Rishabh Chaudhary  1 , Mohd Akhtar Azam  1 , Bhavana Dowand  1 , Alpana Singh  1 , Mujeeba Rehman  1 , Vipul Agarwal  1 , Anand Kumar  1 , Arjun Singh Kaushik  1 , Sukriti Srivastava  1 , Siddhi Srivastava  1 , Vikas Mishra  2
Affiliations

Chronic stress-mediated dysregulations in inflammatory, immune and oxidative circuitry impairs the therapeutic response of methotrexate in experimental autoimmune disease models

Rishabh Chaudhary et al. Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr.

Abstract

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.

Keywords: Autoimmune disease; Chronic stress; Inflammation; Methotrexate; Psoriasis; Rheumatoid arthritis.

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Conflict of interest statement

Declarations. Conflicts of interest: The authors declare no competing interests.

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