The PPAR-α selective agonist WY14643 improves lupus nephritis via the downregulation of the RORγT/STAT3 signaling pathway in MRL/lpr mice.

IF 4.8 2区 医学 Q2 IMMUNOLOGY
International immunopharmacology Pub Date : 2025-01-03 Epub Date: 2024-12-08 DOI:10.1016/j.intimp.2024.113787
Haneen A Al-Mazroua, Ahmed Nadeem, Sabry M Attia, Saleh A Bakheet, Ajaz Ahmad, Mushtaq A Ansari, Khalid E Ibrahim, Hatun A Alomar, Mohammed M Almutairi, Norah K Algarzae, Mohamed A Mahmoud, Marwa H Hussein, Omer M Ahmed, Sheikh F Ahmad
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引用次数: 0

Abstract

Systemic lupus erythematosus (SLE) is a classic autoimmune disorder that mostly affects young women and involves various organs, such as the skin, joints, central nervous system, and kidneys. WY14643, a selective agonist of peroxisome proliferator-activated receptor-α, has previously shown anti-inflammatory effects in various disease models. However, its effects on lupus nephritis are yet to be explored. Therefore, the efficacy of WY14643 on renal biomarkers and lupus nephritis was assessed in MRL/lpr mice. Flow cytometry was used to examinethe effects of WY14643 on the expression of IL-17A, STAT3, RORγT, IL-21, IL-21R, IL-22, and TNF-α in splenic CD4+ T cells. We further investigated the impact of WY14643 on the mRNA expression of IL-17A, STAT3, RORγT, IL-21, IL-21R, IL-22, and TNF-α in kidney tissue via RT-PCR analysis. The administration of WY14643 effectively improved the symptoms of lupus nephritis in MRL/lpr mice. The administration of WY14643 decreased serum albumin, urine protein, serum creatinine, and blood urea nitrogen levels in MRL/lpr mice. WY14643 reduced the levels of inflammatory markers, including CD4+IL-17A+, CD4+STAT3+, CD4+RORγT+, CD4+IL-21+, CD4+IL-21R+, CD4+IL-22+, and CD4+TNF-α+, in the spleen cells of MRL/lpr mice. Additionally, we discovered that the administration of WY14643 resulted in the suppression of mRNA levels of IL-17A, STAT3, RORγT, IL-21, IL-22, and TNF-α. The current work shows that the suppression of inflammatory cells by WY14643 may effectively reduce autoimmune characteristics, such as renal inflammation, in lupus-prone MRL/lpr mice. Therefore, WY14643, being a specific PPAR-α agonist, shows significant potential as a novel therapeutic option for treatingnephritis associated with SLE, offering hope for future treatments in this challenging field.

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来源期刊
CiteScore
8.40
自引率
3.60%
发文量
935
审稿时长
53 days
期刊介绍: International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.
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