CXCR3 antagonist AMG487 suppresses rheumatoid arthritis pathogenesis and progression by shifting the Th17/Treg cell balance

Bakheet, Saleh A.; Ansari, Mushtaq Ahmad; Nadeem, Ahmed; Attia, Sabry M.; Alhoshani, Ali; Gul, Gazala; Alqahtani, Qamraa Hamad; Albekairi, Norah A.; Ibrahim, Khalid E.; Ahmad, Sheikh F.

doi:10.1016/j.cellsig.2019.109395

Cited by 74 publications

(45 citation statements)

References 62 publications

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“…The expression of T-bet, IL-17A, IL-22 and RORγt was down-regulated, and the expression of Foxp3 was up-regulated. Chemokine receptor antagonists have been suggested as an effective strategy for the treatment of RA ( 99 ). Current studies support the hypothesis that Th22/IL-22 plays a pathogenic role in RA pathogenesis, although this mechanism requires further study.…”

Section: Th22 Cells In Autoimmune Diseasesmentioning

confidence: 99%

Role of Th22 Cells in the Pathogenesis of Autoimmune Diseases

et al. 2021

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Upon antigenic stimulation, naïve CD4+T cells differentiate into different subsets and secrete various cytokines to exert biological effects. Th22 cells, a newly identified CD4+T cell subset,are distinct from the Th1, Th2 and Th17 subsets. Th22 cells secrete certain cytokines such as IL-22, IL-13 and TNF-α, but not others, such as IL-17, IL-4, or interferon-γ (IFN-γ), and they express chemokine receptors CCR4, CCR6 and CCR10. Th22 cells were initially found to play a role in skin inflammatory diseases, but recent studies have demonstrated their involvement in the development of various autoimmune diseases. Here, we review research advances in the origin, characteristics and effector mechanisms of Th22 cells, with an emphasis on the role of Th22 cells and their main effector cytokine IL-22 in the pathogenesis of autoimmune diseases. The findings presented here may facilitate the development of new therapeutic strategies for targeting these diseases.

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Section: Th22 Cells In Autoimmune Diseasesmentioning

confidence: 99%

Role of Th22 Cells in the Pathogenesis of Autoimmune Diseases

et al. 2021

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“…Further experiments demonstrated that Tregs deletion abrogated the role of CXCR3 in mitigating kidney IRI, demonstrating that CXCR3 ameliorated kidney IRI through expansion of Tregs. However, Bakheet et al (35) found that administration of AMG487, an antagonist of CXCR3, to mice with collagen-induced arthritis significantly decreased histological inflammatory damage, the percentage of Th1, Th17 and Th22 cells, and increased Tregs. The different tissue contents and conditions may cause this disparity.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 alleviates renal ischemia‑reperfusion injury via increase of Tregs

Xian

et al. 2021

Mol Med Rep

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Increasing evidence has demonstrated that regulatory T cells (Tregs) suppress innate immunity, as well as protect the kidneys from ischemia-reperfusion injury (IRI) and offer a potentially effective strategy to prevent or alleviate renal IRI. The present study explored whether C-X-C motif chemokine receptor 3 (CXCR3) alleviated renal IRI by increasing Tregs. Male C57BL/6J mice were divided into sham-surgery, IRI, CXCR3 overexpression (OE-CXCR3)+IRI, PC61+IRI and OE-CXCR3+PC61+IRI groups. Histopathological examination of the kidney was carried out using hematoxylin-eosin and Masson staining. The levels of serum creatinine (Scr) and blood urea nitrogen (BUN) were measured. Blood and kidney levels of IL-6, TNF-α, C-C motif chemokine ligand (CCL)-2 and IL-10 were detected by ELISA and western blotting. The levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in kidney tissues were also measured to assess oxidative stress. The population of Tregs in the kidney was assessed using flow cytometry. The results demonstrated that administration of OE-CXCR3 to IRI mice significantly decreased the levels of Scr, BUN, IL-6, TNF-α, CCL-2 and MDA, increased the levels of IL-10, SOD and GSH-Px, and mitigated the morphologic injury and fibrosis induced by IR compared with the IRI group. In addition, administration of OE-CXCR3 induced significant reductions in the expression levels of fibrosis-related markers, including fibronectin and type IV collagen, and increased the number of Tregs. These roles of OE-CXCR3 were significantly neutralized following deletion of Tregs with PC61 (anti-CD25 antibody). Together, the present study demonstrated that injection of OE-CXCR3 lentiviral vectors into animal models can alleviate renal IRI by increasing the number of Tregs. The results may be a promising approach for the treatment of renal IRI.

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“…Chronic inflammation caused by disorganized immune activation and correlated systemic abnormalities might underpin the common pathogenesis of psoriasis and related diseases. There is evidence that an imbalance between different T cells, e.g., T helper cells 17 (Th17) vs. regulatory T cells (Treg) and abnormal cytokine production are the driving forces in common for the progression and development of mental disorder and immune system disease ( Ahmad et al, 2017 ; Ahmad et al, 2017 ; Bakheet et al, 2019 ; Ahmad et al, 2020 ). Many compounds, which have been shown to have promising effects in multiple immune-mediated inflammatory disorders such as asthma, rheumatoid arthritis, and alcoholic liver disease, have therapeutic potential in psoriatic inflammation as well ( Alzahrani et al, 2019 ; Al-Harbi et al, 2020 ; Nadeem et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Systems Pharmacology Approach and Experiment Evaluation Reveal Multidimensional Treatment Strategy of LiangXueJieDu Formula for Psoriasis

et al. 2021

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Clinical studies have demonstrated the anti-psoriatic effect of the LiangXueJieDu (LXJD) herbal formula. However, the systemic mechanism and the targets of the LXJD formula have not yet been elucidated. In the present study, a systems pharmacology approach, metabolomics, and experimental evaluation were employed. First, by systematic absorption-distribution-metabolism-excretion (ADME) analysis, 144 active compounds with satisfactory pharmacokinetic properties were identified from 12 herbs of LXJD formula using the TCMSP database. These active compounds could be linked to 125 target proteins involved in the pathological processes underlying psoriasis. Then, the networks constituting the active compounds, targets, and diseases were constructed to decipher the pharmacological actions of this formula, indicating its curative effects in psoriasis treatment and related complications. The psoriasis-related pathway comprising several regulatory modules demonstrated the synergistic mechanisms of LXJD formula. Furthermore, the therapeutic effect of LXJD formula was validated in a psoriasis-like mouse model. Consistent with the systems pharmacology analysis, LXJD formula ameliorated IMQ-induced psoriasis-like lesions in mice, inhibited keratinocyte proliferation, improved keratinocyte differentiation, and suppressed the infiltration of CD3+ T cells. Compared to the model group, LXJD formula treatment remarkably reduced the expression of inflammatory cytokines and factors, such as IL-1β, IL-6, TNF-α, Cox2, and inhibited the phosphorylation of p-P65, p-IқB, p-ERK, p-P38, p-PI3K, p-AKT, indicating that LXJD formula exerts its therapeutic effect by inhibiting the MAPK, PI3K/AKT, and NF-қB signaling pathways. The metabolic changes in the serum of psoriasis patients were evaluated by liquid chromatography coupled with orbitrap mass spectrometry (LC-MS). The LXJD formula improved two perturbed metabolic pathways of glycerophospholipid metabolism and steroid hormone biosynthesis. Overall, this study revealed the complicated anti-psoriatic mechanism of LXJD formula and also offered a reliable strategy to elucidate the complex therapeutic mechanism of this Chinese herbal formula in psoriasis from a holistic perspective.

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CXCR3 antagonist AMG487 suppresses rheumatoid arthritis pathogenesis and progression by shifting the Th17/Treg cell balance

Cited by 74 publications

References 62 publications

Role of Th22 Cells in the Pathogenesis of Autoimmune Diseases

Role of Th22 Cells in the Pathogenesis of Autoimmune Diseases

CXCR3 alleviates renal ischemia‑reperfusion injury via increase of Tregs

Systems Pharmacology Approach and Experiment Evaluation Reveal Multidimensional Treatment Strategy of LiangXueJieDu Formula for Psoriasis

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