Skip to main content

Advertisement

SpringerLink
Log in

CXCL9 and its Receptor CXCR3, an Important Link Between Inflammation and Cardiovascular Risks in RA Patients

  • RESEARCH
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Cardiovascular disease (CVD) is the most common cause of mortality in rheumatoid arthritis (RA), and Inflammation has a decisive role in its pathogenesis. CXCL9 contributes to multi aspects of inflammatory reactions associated with the pathogenesis of CVD. In the current study, we evaluated the association of plasma CXCL9 and CXCR3 gene expression with Cardiovascular risk factors in RA patients for the first time. Thirty newly diagnosed, 30 on-treatment RA patients, and 30 healthy subjects were recruited in this study. The plasma concentration of CXCL9 and CXCR3 gene expression were measured using ELISA and Real-Time PCR, respectively. The CVD risk was evaluated using Framingham Risk Score (FRS) and Systematic Coronary Risk Evaluation (SCORE). The plasma levels of CXCL9 were significantly higher in the newly diagnosed and on-treatment RA patients compared to the control group (P < 0.0001 and P < 0.001, respectively). Also, The CXCR3 gene expression was strongly elevated in newly diagnosed and on-treatment patients (P < 0.001 and P < 0.01, respectively). The CXCL9 and CXCR3 were significantly associated with RA disease activity (P = 0.0005, r = 0.436; P = 0.0002, r = 0.463, respectively). The FRS was remarkably higher in newly diagnosed and on-treatment patients (P = 0.014 and P = 0.035, respectively). The CXCR3 gene expression significantly correlated with age, systolic blood pressure, FRS, and SCORE (P = 0.020, r = 0.298; P = 0.006, r = 0.346; P = 0.006, r = 0.349; P = 0.007, r = 0.341, respectively). The CXCL9 plasma concentration had a significant negative correlation with plasma HDL and LDL levels (P = 0.033, r = -0.275; P = 0.021, r = -0.296, respectively). CXCL9 and CXCR3 correlates with different variables of CVD in RA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

The data generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

RA:

Rheumatoid Arthritis

CVD:

Cardiovascular Disease

SCORE:

Systematic Coronary Risk Evaluation

FRS:

Framingham Risk Score

EULAR:

European Alliance of Associations for Rheumatology

BMI:

Body mass index

CXCL9:

Chemokine (C-X-C motif) ligand 9

iAge:

Age-related chronic inflammation

IFN-γ:

Interferon-gamma

CXCR3:

C-X-C Motif Chemokine Receptor 3

MI:

Myocardial infarction

LVD:

Left ventricular dysfunction

ACR:

American college of rheumatology

DMARD:

Disease modified anti-rheumatoid drugs

BPS:

Systolic blood pressure

BPD:

Diastolic blood pressure

References

  1. Fearon, U., et al. 2022. Cellular metabolic adaptations in rheumatoid arthritis and their therapeutic implications. Nature Reviews Rheumatology 18 (7): 398–414.

    Article  CAS  PubMed  Google Scholar 

  2. Romão, V.C., and J.E. Fonseca. 2021. Etiology and risk factors for rheumatoid arthritis: a state-of-the-art review. Frontiers in Medicine 8: 689698.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bauer, M.E. 2020. Accelerated immunosenescence in rheumatoid arthritis: impact on clinical progression. Immunity & Ageing 17: 6.

    Article  CAS  Google Scholar 

  4. Almutairi, K., et al. 2021. The global prevalence of rheumatoid arthritis: a meta-analysis based on a systematic review. Rheumatology international 41 (5): 863–877.

    Article  PubMed  Google Scholar 

  5. Finckh, A., et al. 2022. Global epidemiology of rheumatoid arthritis. Nature Reviews Rheumatology 18 (10): 591–602.

    PubMed  Google Scholar 

  6. Conforti, A., et al. 2021. Beyond the joints, the extra-articular manifestations in rheumatoid arthritis. Autoimmunity Reviews 20 (2): 102735.

    Article  PubMed  Google Scholar 

  7. Karami, J., et al. 2019. Genetic implications in the pathogenesis of rheumatoid arthritis; an updated review. Gene 702: 8–16.

    Article  CAS  PubMed  Google Scholar 

  8. Figus, F.A., et al. 2021. Rheumatoid arthritis: Extra-articular manifestations and comorbidities. Autoimmunity Reviews 20 (4): 102776.

    Article  CAS  PubMed  Google Scholar 

  9. Sparks, J.A. 2019. Rheumatoid arthritis. Annals of Internal Medicine 170 (1): Itc1–Itc16.

    Article  PubMed  Google Scholar 

  10. Gulati, M., Z. Farah, and M. Mouyis. 2018. Clinical features of rheumatoid arthritis. Medicine 46 (4): 211–215.

    Article  Google Scholar 

  11. Semb, A.G., et al. 2020. Atherosclerotic cardiovascular disease prevention in rheumatoid arthritis. Nature Reviews Rheumatology 16 (7): 361–379.

    Article  PubMed  Google Scholar 

  12. Frąk, W., et al. 2022. Pathophysiology of cardiovascular diseases: new insights into molecular mechanisms of atherosclerosis, arterial hypertension, and coronary artery disease. Biomedicines 10 (8): 1938.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Agca, R., et al. 2017. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Annals of the Rheumatic Diseases 76 (1): 17–28.

    Article  CAS  PubMed  Google Scholar 

  14. Santos-Moreno, P., et al. 2021. Inflammaging as a link between autoimmunity and cardiovascular disease: the case of rheumatoid arthritis. RMD Open 7 (1): e001470.

    Article  PubMed  PubMed Central  Google Scholar 

  15. England, B.R., et al. 2018. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ 361: k1036.

    Article  PubMed  PubMed Central  Google Scholar 

  16. DeMizio, D.J., and L.B. Geraldino-Pardilla. 2020. Autoimmunity and inflammation link to cardiovascular disease risk in rheumatoid arthritis. Rheumatology and Therapy 7 (1): 19–33.

    Article  PubMed  Google Scholar 

  17. Sayed, N., et al. 2021. An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nature Aging 1 (7): 598–615.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Pournazari, M., et al. 2022. Increased plasma levels of CCL20 in peripheral blood of rheumatoid arthritis patients and its association with clinical and laboratory parameters. Clinical Rheumatology 41: 265–270.

    Article  PubMed  Google Scholar 

  19. Choy, E.H., and G.S. Panayi. 2001. Cytokine pathways and joint inflammation in rheumatoid arthritis. New England Journal of Medicine 344 (12): 907–916.

    Article  CAS  PubMed  Google Scholar 

  20. Szekanecz, Z., J. Kim, and A.E. Koch. 2003. Chemokines and chemokine receptors in rheumatoid arthritis. In Seminars in immunology. Elsevier.

    Google Scholar 

  21. García-Vicuña, R., et al. 2004. CC and CXC chemokine receptors mediate migration, proliferation, and matrix metalloproteinase production by fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis & Rheumatism 50 (12): 3866–3877.

    Article  Google Scholar 

  22. Lu, X., et al. 2022. The role of CXC chemokines in cardiovascular diseases. Frontiers in Pharmacology 12: 3830.

    Article  Google Scholar 

  23. Altara, R., et al. 2015. Left ventricular dysfunction and CXCR3 ligands in hypertension: from animal experiments to a population-based pilot study. PLoS ONE 10 (10): e0141394.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lin, C.F., et al. 2019. Potential effects of CXCL9 and CCL20 on cardiac fibrosis in patients with myocardial infarction and isoproterenol-treated rats. Journal of Clinical Medicine 8 (5): 659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pfaffl, M.W. 2001. A new mathematical model for relative quantification in real-time RT–PCR. Nucleic Acids Research 29 (9): e45–e45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Prevoo, M., et al. 1995. Modified disease activity scores that include twenty-eight-joint counts development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 38 (1): 44–48.

    Article  CAS  Google Scholar 

  27. Goff, D.C., Jr., et al. 2014. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129 (25_suppl_2): S49–S73.

    Article  PubMed  Google Scholar 

  28. Mahmood, S.S., et al. 2014. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet 383 (9921): 999–1008.

    Article  PubMed  Google Scholar 

  29. Truett, J., J. Cornfield, and W. Kannel. 1967. A multivariate analysis of the risk of coronary heart disease in Framingham. Journal of Chronic Diseases 20 (7): 511–524.

    Article  CAS  PubMed  Google Scholar 

  30. Conroy, R.M., et al. 2003. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. European Heart Journal 24 (11): 987–1003.

    Article  CAS  PubMed  Google Scholar 

  31. Kuan, W.P., et al. 2010. CXCL 9 and CXCL 10 as Sensitive markers of disease activity in patients with rheumatoid arthritis. The Journal of Rheumatology 37 (2): 257–264.

    Article  CAS  PubMed  Google Scholar 

  32. Pandya, J.M., et al. 2017. Blood chemokine profile in untreated early rheumatoid arthritis: CXCL10 as a disease activity marker. Arthritis Research & Therapy 19 (1): 20.

    Article  Google Scholar 

  33. Gravallese, E.M., and G.S. Firestein. 2023. Rheumatoid arthritis—Common origins, divergent mechanisms. New England Journal of Medicine 388 (6): 529–542.

    Article  CAS  PubMed  Google Scholar 

  34. Al-Jaberi, L., M.M. Simonds, and A.M.C. Brescia. 2022. CCL24, CXCL9 and CXCL10 are increased in synovial fluid in patients with juvenile idiopathic arthritis requiring advanced treatment. Rheumatology 62 (7): 2594–2600.

    Article  Google Scholar 

  35. Van Raemdonck, K., et al. 2015. CXCR3 ligands in disease and therapy. Cytokine & Growth Factor Reviews 26 (3): 311–327.

    Article  Google Scholar 

  36. Ruschpler, P., et al. 2003. High CXCR3 expression in synovial mast cells associated with CXCL9 and CXCL10 expression in inflammatory synovial tissues of patients with rheumatoid arthritis. Arthritis Research & Therapy 5: R241.

    Article  CAS  Google Scholar 

  37. Wagan, A.A., et al. 2016. Cardiovascular risk score in rheumatoid arthritis. Pakistan Journal of Medical Sciences 32 (3): 534.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Altara, R., et al. 2016. Emerging importance of chemokine receptor CXCR3 and its ligands in cardiovascular diseases. Clinical Science 130 (7): 463–478.

    Article  CAS  PubMed  Google Scholar 

  39. Mach, F., et al. 1999. Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells. The Journal of Clinical Investigation 104 (8): 1041–1050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. O’Neill, F., et al. 2017. Anti-inflammatory treatment improves high-density lipoprotein function in rheumatoid arthritis. Heart 103 (10): 766–773.

    Article  CAS  PubMed  Google Scholar 

  41. Samimi, Z., et al. 2021. The association between the plasma sugar and lipid profile with the gene expression of the regulatory protein of mTOR (Raptor) in patients with rheumatoid arthritis. Immunological Investigations 50 (6): 597–608.

    Article  CAS  PubMed  Google Scholar 

  42. Desai, R.J., et al. 2015. Disease-modifying antirheumatic drug use and the risk of incident hyperlipidemia in patients with early rheumatoid arthritis: a retrospective cohort study. Arthritis Care & Research 67 (4): 457–466.

    Article  CAS  Google Scholar 

  43. Matarese, G. 2023. The link between obesity and autoimmunity. Science 379 (6639): 1298–1300.

    Article  CAS  PubMed  Google Scholar 

  44. Rudominer, R.L., et al. 2009. Independent association of rheumatoid arthritis with increased left ventricular mass but not with reduced ejection fraction. Arthritis & Rheumatism 60 (1): 22–29.

    Article  Google Scholar 

  45. Smolen, J.S., et al. 2023. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Annals of the Rheumatic Diseases 82 (1): 3–18.

    Article  CAS  PubMed  Google Scholar 

  46. Bonfante, H.D.L., et al. 2017. CCL 2, CXCL 8, CXCL 9 and CXCL 10 serum levels increase with age but are not altered by treatment with hydroxychloroquine in patients with osteoarthritis of the knees. International Journal of Rheumatic Diseases 20 (12): 1958–1964.

    Article  CAS  PubMed  Google Scholar 

  47. Brynedal, B., et al. 2023. Molecular signature of methotrexate response among rheumatoid arthritis patients. Frontiers in Medicine 10: 1146353.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kotrych, D., et al. 2015. Lack of association between CXCL9 and CXCL10 gene polymorphisms and the outcome of rheumatoid arthritis treatment with methotrexate. European Review for Medical and Pharmacological Sciences 19 (16): 3037–3040.

    CAS  PubMed  Google Scholar 

  49. England, B.R., et al. 2018. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. The BMJ 361: k1036.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Atzeni, F., et al. 2021. Cardiovascular effects of approved drugs for rheumatoid arthritis. Nature Reviews Rheumatology 17 (5): 270–290.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We appreciate the support of the deputy of research and technology of the Kermanshah University of Medical Sciences for financial support of this work.

Funding

This work was supported by the Kermanshah University of Medical Sciences grant number (4010153).

Author information

Authors and Affiliations

  1. Immunology Department, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Afsaneh Shamsi, Seyed Askar Roghani, Masood Ghasemzade Soroush & Mahdi Taghadosi

  2. Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Seyed Askar Roghani & Nader Salari

  3. Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Seyed Askar Roghani, Zahra Abdan, Parviz Soufivand & Mehran Pournazari

  4. Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Fariborz Bahrehmand

  5. Department of Medical Biotechnology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Ali Vafaei

  6. Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Nader Salari

Authors
  1. Afsaneh Shamsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seyed Askar Roghani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zahra Abdan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Parviz Soufivand
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mehran Pournazari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fariborz Bahrehmand
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ali Vafaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nader Salari
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masood Ghasemzade Soroush
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mahdi Taghadosi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Mahdi Taghadosi: contributed to the concept and idea design, checked the final results, and final approval of the article. Afsaneh Shamsi: acquisition of data, performed research and experiment and wrote the manuscript. Parviz Soufivand and Mehran Pournazari: patient diagnosis and provided clinical data. Zahra Abdan and Nader Salari: summarized and analyzed the data. Seyed Askar Roghani and Fariborz Bahrehmand: performed an experiment. Masood Ghasemzade Soroush and Ali Vafaei: contributed to research and provided clinical data, respectively. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Mahdi Taghadosi.

Ethics declarations

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Kermanshah University of Medical Sciences (Approval No: IR.KUMS.MED.REC.1401.017).

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent to Publication

Not applicable.

Competing Interest

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shamsi, A., Roghani, S.A., Abdan, Z. et al. CXCL9 and its Receptor CXCR3, an Important Link Between Inflammation and Cardiovascular Risks in RA Patients. Inflammation 46, 2374–2385 (2023). https://doi.org/10.1007/s10753-023-01884-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-023-01884-5

KEY WORDS

Search

Navigation