Chronic Stress-mediated Dysregulations in Inflammatory, Immune and Oxidative Circuitry Impairs the Therapeutic Response of Methotrexate in Experimental Autoimmune Disease Models

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 2024 Oct 25

PMID 39453502

Authors

Rishabh Chaudhary

Mohd Akhtar Azam

Bhavana Dowand

Alpana Singh

Mujeeba Rehman

Vipul Agarwal

Anand Kumar

Arjun Singh Kaushik

Sukriti Srivastava

Siddhi Srivastava

Vikas Mishra

Affiliations

Soon will be listed here.

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.

References

Acabchuk R, Kamath J, Salamone J, Johnson B . Stress and chronic illness: The inflammatory pathway. Soc Sci Med. 2017; 185:166-170. PMC: 8570552. DOI: 10.1016/j.socscimed.2017.04.039. View

Adefegha S, Okeke B, Oboh G, Ijomone O, Oyeleye S . Modulatory effect of eugenol on arginase, nucleotidase, and adenosine deaminase activities of platelets in a carrageenan-induced arthritis rat model: A possible anti-arthritic mechanism of eugenol. Biomed Pharmacother. 2018; 106:1616-1623. DOI: 10.1016/j.biopha.2018.07.143. View

Agarwal V, Kaushik A, Rehman M, Chaudhary R, Jawaid T, Kamal M . Interleukin-6 expression and its modulation by diacerein in a rat model of chronic stress induced cardiac dysfunction. Heliyon. 2021; 7(12):e08522. PMC: 8665349. DOI: 10.1016/j.heliyon.2021.e08522. View

Agorastos A, Chrousos G . The neuroendocrinology of stress: the stress-related continuum of chronic disease development. Mol Psychiatry. 2021; 27(1):502-513. DOI: 10.1038/s41380-021-01224-9. View

Avitsur R, Stark J, Dhabhar F, Sheridan J . Social stress alters splenocyte phenotype and function. J Neuroimmunol. 2002; 132(1-2):66-71. DOI: 10.1016/s0165-5728(02)00310-7. View

Barrett T, Corr E, van Solingen C, Schlamp F, Brown E, Koelwyn G . Chronic stress primes innate immune responses in mice and humans. Cell Rep. 2021; 36(10):109595. PMC: 8493594. DOI: 10.1016/j.celrep.2021.109595. View

Benjamin C, Stowe R, St John L, Sams C, Mehta S, Crucian B . Decreases in thymopoiesis of astronauts returning from space flight. JCI Insight. 2016; 1(12):e88787. PMC: 5033888. DOI: 10.1172/jci.insight.88787. View

Bhatt S, Nagappa A, Patil C . Role of oxidative stress in depression. Drug Discov Today. 2020; 25(7):1270-1276. DOI: 10.1016/j.drudis.2020.05.001. View

Biltz R, Sawicki C, Sheridan J, Godbout J . The neuroimmunology of social-stress-induced sensitization. Nat Immunol. 2022; 23(11):1527-1535. PMC: 10000282. DOI: 10.1038/s41590-022-01321-z. View

10.

Bisht K, Sharma K, Tremblay M . Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress. Neurobiol Stress. 2018; 9:9-21. PMC: 6035903. DOI: 10.1016/j.ynstr.2018.05.003. View

11.

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

12.

Bronte V, Pittet M . The spleen in local and systemic regulation of immunity. Immunity. 2013; 39(5):806-18. PMC: 3912742. DOI: 10.1016/j.immuni.2013.10.010. View

13.

Chan K, Poller W, Swirski F, Russo S . Central regulation of stress-evoked peripheral immune responses. Nat Rev Neurosci. 2023; 24(10):591-604. PMC: 10848316. DOI: 10.1038/s41583-023-00729-2. View

14.

Chaudhary R, Prasad A, Agarwal V, Rehman M, Kumar A, Kaushik A . Chronic stress predisposes to the aggravation of inflammation in autoimmune diseases with focus on rheumatoid arthritis and psoriasis. Int Immunopharmacol. 2023; 125(Pt A):111046. DOI: 10.1016/j.intimp.2023.111046. View

15.

Chida Y, Sudo N, Kubo C . Social isolation stress exacerbates autoimmune disease in MRL/lpr mice. J Neuroimmunol. 2004; 158(1-2):138-44. DOI: 10.1016/j.jneuroim.2004.09.002. View

16.

Cronstein B, Aune T . Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol. 2020; 16(3):145-154. DOI: 10.1038/s41584-020-0373-9. View

17.

Crum R, Hall K, Pineda Molina C, Hussey G, Graham E, Li H . Immunomodulatory matrix-bound nanovesicles mitigate acute and chronic pristane-induced rheumatoid arthritis. NPJ Regen Med. 2022; 7(1):13. PMC: 8810774. DOI: 10.1038/s41536-022-00208-9. View

18.

Deng C, Zhang Q, He P, Zhou B, He K, Sun X . Targeted apoptosis of macrophages and osteoclasts in arthritic joints is effective against advanced inflammatory arthritis. Nat Commun. 2021; 12(1):2174. PMC: 8042091. DOI: 10.1038/s41467-021-22454-z. View

19.

Devaki M, Nirupama R, Yajurvedi H . Chronic stress-induced oxidative damage and hyperlipidemia are accompanied by atherosclerotic development in rats. Stress. 2012; 16(2):233-43. DOI: 10.3109/10253890.2012.719052. View

20.

Dhabhar F . Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation. 2009; 16(5):300-17. PMC: 2790771. DOI: 10.1159/000216188. View