Skip to main content

Advertisement

SpringerLink
Log in

Pro-resolving and anti-inflammatory effects of resolvins and protectins in rheumatoid arthritis

  • Review
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Rheumatoid arthritis (RA) is typified by persistent joint inflammation, which leads to the deterioration of bone and cartilage and a reduction in overall quality of life. The global prevalence of pain as a primary symptom in RA is influenced by the interplay between inflammation and its resolution. The identification of a family of lipid mediators known as specialized pro-resolving mediators (SPM)s has contributed to the progress of our comprehension of inflammatory conditions. SPMs have been observed to trigger the process of inflammation resolution, thereby reinstating the homeostasis of the inflammatory response. Autacoids are synthesized through the stereo-selective transformation of essential fatty acids, resulting in molecules dynamically modulated during inflammation and possessing strong immunoregulatory properties. This review delves into the available evidence that supports the involvement of certain SPM as protective lipids, biomarkers with potential, and therapeutic targets in the context of 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

Enquiries about data availability should be directed to the authors.

References

  • Amani F, Hoseinzadeh S, Sabzvari A, Avesta L, Kahnamouei-Aghdam F, Barak M (2015) Awareness rate of Ardabil city people about multiple sclerosis. International Journal of Advances in Medicine 2(2):156–159

    Article  Google Scholar 

  • Arnardottir HH, Dalli J, Norling LV, Colas RA, Perretti M, Serhan CN (2016) Resolvin D3 is dysregulated in arthritis and reduces arthritic inflammation. J Immunol 197(6):2362–2368

    Article  CAS  PubMed  Google Scholar 

  • Ashjari D, Karamali N, Rajabinejad M, Hassani SS, Hezarkhani LA, Afshari D, Karaji AG, Salari F, Rezaiemanesh A (2022) The axis of long non-coding RNA MALAT1/miR-1-3p/CXCR4 is dysregulated in patients with diabetic neuropathy. Heliyon 8(3):e09178. https://doi.org/10.1016/j.heliyon.2022.e09178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barden AE, Mas E, Mori TA (2016) n-3 Fatty acid supplementation and proresolving mediators of inflammation. Curr Opin Lipidol 27(1):26–32

    Article  CAS  PubMed  Google Scholar 

  • Benabdoun HA, Kulbay M, Rondon E-P, Vallières F, Shi Q, Fernandes J, Fahmi H, Benderdour M (2019) In vitro and in vivo assessment of the proresolutive and antiresorptive actions of resolvin D1: relevance to arthritis. Arthritis Res Ther 21(1):1–14

    Article  Google Scholar 

  • Benabdoune H, Rondon E-P, Shi Q, Fernandes J, Ranger P, Fahmi H, Benderdour M (2016) The role of resolvin D1 in the regulation of inflammatory and catabolic mediators in osteoarthritis. Inflamm Res 65:635–645

    Article  CAS  PubMed  Google Scholar 

  • Burmester GR, Pope JE (2017) Novel treatment strategies in rheumatoid arthritis. The Lancet 389(10086):2338–2348

    Article  Google Scholar 

  • Chiurchiù V, Leuti A, Dalli J, Jacobsson A, Battistini L, Maccarrone M, Serhan CN (2016) Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses. Science Translational Medicine 8(353):353ra111-353ra111

    Article  PubMed  PubMed Central  Google Scholar 

  • Dalli J, Chiang N, Serhan CN (2015) Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. Nat Med 21(9):1071–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dalli J, Colas RA, Serhan CN (2013) Novel n-3 immunoresolvents: structures and actions. Sci Rep 3(1):1–15

    Article  Google Scholar 

  • Dalli J, Serhan CN (2012) Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood, the Journal of the American Society of Hematology 120(15):e60–e72

    CAS  Google Scholar 

  • de Molon RS, Thurlings RM, Walgreen B, Helsen MM, van der Kraan PM, Cirelli JA, Koenders MI (2019) Systemic Resolvin E1 (RvE1) treatment does not ameliorate the severity of collagen-induced arthritis (CIA) in mice: a randomized, prospective, and controlled proof of concept study. Mediators Inflamm 2019:5689465. https://doi.org/10.1155/2019/5689465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duvall MG, Levy BD (2016) DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation. Eur J Pharmacol 785:144–155. https://doi.org/10.1016/j.ejphar.2015.11.001

    Article  CAS  PubMed  Google Scholar 

  • Flower RJ, Perretti M (2005) Controlling inflammation: a fat chance? J Exp Med 201(5):671–674. https://doi.org/10.1084/jem.20050222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Y, Chen S, Vafaei S, Zhong X (2020) Tumor-infiltrating immune cell signature predicts the prognosis and chemosensitivity of patients with pancreatic ductal adenocarcinoma. Front Oncol 10:557638

    Article  PubMed  PubMed Central  Google Scholar 

  • Gomez EA, Colas RA, Souza PR, Hands R, Lewis MJ, Bessant C, Pitzalis C, Dalli J (2020) Blood pro-resolving mediators are linked with synovial pathology and are predictive of DMARD responsiveness in rheumatoid arthritis. Nat Commun 11(1):5420. https://doi.org/10.1038/s41467-020-19176-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hashimoto A, Hayashi I, Murakami Y, Sato Y, Kitasato H, Matsushita R, Iizuka N, Urabe K, Itoman M, Hirohata S (2007) Antiinflammatory mediator lipoxin A4 and its receptor in synovitis of patients with rheumatoid arthritis. J Rheumatol 34(11):2144–2153

    CAS  PubMed  Google Scholar 

  • Hong S, Gronert K, Devchand PR, Moussignac R-L, Serhan CN (2003) Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells: autacoids in anti-inflammation. J Biol Chem 278(17):14677–14687

    Article  CAS  PubMed  Google Scholar 

  • Iranshahi N, Assar S, Amiri SM, Zafari P, Fekri A, Taghadosi M (2019) Decreased gene expression of Epstein-Barr virus-induced gene 3 (EBI-3) may contribute to the pathogenesis of rheumatoid arthritis. Immunol Invest 48(4):367–377

    Article  CAS  PubMed  Google Scholar 

  • Jin S, Sun S, Ling H, Ma J, Zhang X, Xie Z, Zhan N, Zheng W, Li M, Qin Y, Zhao H, Chen Y, Yang X, Wang J (2021) Protectin DX restores Treg/T(h)17 cell balance in rheumatoid arthritis by inhibiting NLRP3 inflammasome via miR-20a. Cell Death Dis 12(3):280. https://doi.org/10.1038/s41419-021-03562-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Körner A, Zhou E, Müller C, Mohammed Y, Herceg S, Bracher F, Rensen PC, Wang Y, Mirakaj V, Giera M (2019) Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution. Proc Natl Acad Sci 116(41):20623–20634

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee H-N, Surh Y-J (2012) Therapeutic potential of resolvins in the prevention and treatment of inflammatory disorders. Biochem Pharmacol 84(10):1340–1350. https://doi.org/10.1016/j.bcp.2012.08.004

    Article  CAS  PubMed  Google Scholar 

  • Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN (2001) Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2(7):612–619

    Article  CAS  PubMed  Google Scholar 

  • Li C, Lin L, Zhang L, Xu R, Chen X, Ji J, Li Y (2021) Long noncoding RNA p21 enhances autophagy to alleviate endothelial progenitor cells damage and promote endothelial repair in hypertension through SESN2/AMPK/TSC2 pathway. Pharmacol Res 173:105920

    Article  CAS  PubMed  Google Scholar 

  • Li L, Xu H, Qu L, Nisar M, Nisar MF, Liu X, Xu K (2023) Water extracts of Polygonum Multiflorum Thunb. and its active component emodin relieves osteoarthritis by regulating cholesterol metabolism and suppressing chondrocyte inflammation. Acupuncture and Herbal Medicine 3(2):96–106

    Article  Google Scholar 

  • Lima-Garcia JF, Dutra RC, da Silva K, Motta EM, Campos MM, Calixto JB (2011) The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats. Br J Pharmacol 164(2):278–293. https://doi.org/10.1111/j.1476-5381.2011.01345.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin W, Huang J, Guo S, Zhao M, Chen X, Shang Q, Zhang R, Liao G, Zheng J, Liao Y (2023) A tunable fluorescent probe for superoxide anion detection during inflammation caused by Treponema pallidum. Journal of Materials Chemistry B 11(20):4523–4528

    Article  CAS  PubMed  Google Scholar 

  • Littlejohn EA, Monrad SU (2018) Early diagnosis and treatment of rheumatoid arthritis. Primary Care: Clinics in Office Practice 45(2):237–255

    Article  PubMed  Google Scholar 

  • Lou J-S, Zhao L-P, Huang Z-H, Chen X-Y, Xu J-T, Tai WC-S, Tsim KW, Chen Y-T, Xie T (2021) Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer. Phytomedicine 80:153370

    Article  CAS  PubMed  Google Scholar 

  • Mohsenzadegan M, Razmi M, Vafaei S, Abolhasani M, Madjd Z, Saeednejad Zanjani L, Sharifi L (2022) Co-expression of cancer-testis antigens of MAGE-A6 and MAGE-A11 is associated with tumor aggressiveness in patients with bladder cancer. Sci Rep 12(1):599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Norling LV, Headland SE, Dalli J, Arnardottir HH, Haworth O, Jones HR, Irimia D, Serhan CN, Perretti M (2016) Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis. JCI Insight 1(5):e85922. https://doi.org/10.1172/jci.insight.85922

    Article  PubMed  PubMed Central  Google Scholar 

  • Özdemir RBÖ, Gündüz ÖS, Özdemir AT, Akgül Ö (2020) Low levels of pro-resolving lipid mediators lipoxin-A4, resolvin-D1 and resolvin-E1 in patients with rheumatoid arthritis. Immunol Lett 227:34–40

    Article  PubMed  Google Scholar 

  • Qin X, Zhang K, Fan Y, Fang H, Nie Y, Wu X-L (2022) The bacterial MtrAB two-component system regulates the cell wall homeostasis responding to environmental alkaline stress. Microbiology Spectrum 10(5):e02311-02322

    Article  PubMed  PubMed Central  Google Scholar 

  • Qu Q, Xuan W, Fan GH (2015) Roles of resolvins in the resolution of acute inflammation. Cell Biol Int 39(1):3–22

    Article  CAS  PubMed  Google Scholar 

  • Samimi Z, Kardideh B, Zafari P, Bahrehmand F, Roghani SA, Taghadosi M (2019) The impaired gene expression of adenosine monophosphate-activated kinase (AMPK), a key metabolic enzyme in leukocytes of newly diagnosed rheumatoid arthritis patients. Mol Biol Rep 46:6353–6360

    Article  CAS  PubMed  Google Scholar 

  • Scherer HU, Häupl T, Burmester GR (2020) The etiology of rheumatoid arthritis. J Autoimmun 110:102400

    Article  CAS  PubMed  Google Scholar 

  • Scott DL, Wolfe F, Huizinga TW (2010) Rheumatoid arthritis. Lancet 376(9746):1094–1108. https://doi.org/10.1016/s0140-6736(10)60826-4

    Article  PubMed  Google Scholar 

  • Serhan CN (2011) The resolution of inflammation: the devil in the flask and in the details. FASEB J 25(5):1441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Serhan CN (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510(7503):92–101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Serhan CN, Chiang N, Dalli J, Levy BD (2014) Lipid mediators in the resolution of inflammation. Cold Spring Harb Perspect Biol 7(2):a016311. https://doi.org/10.1101/cshperspect.a016311

    Article  PubMed  Google Scholar 

  • Serhan CN, Dalli J, Colas RA, Winkler JW, Chiang N (2015) Protectins and maresins: new pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome. Biochimica Et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1851(4):397–413

    Article  CAS  PubMed  Google Scholar 

  • Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, Moussignac R-L (2002) Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 196(8):1025–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stephenson DJ, Hoeferlin LA, Chalfant CE (2017) Lipidomics in translational research and the clinical significance of lipid-based biomarkers. Transl Res 189:13–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sui X, Zhang R, Liu S, Duan T, Zhai L, Zhang M, Han X, Xiang Y, Huang X, Lin H (2018) RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer. Front Pharmacol 9:1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun W, Ma J, Zhao H, Xiao C, Zhong H, Ling H, Xie Z, Tian Q, Chen H, Zhang T (2020) Resolvin D1 suppresses pannus formation via decreasing connective tissue growth factor caused by upregulation of miRNA-146a-5p in rheumatoid arthritis. Arthritis Res Ther 22(1):1–14

    Article  Google Scholar 

  • Swanson KV, Deng M, Ting JP-Y (2019) The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19(8):477–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian Z, Zhang Y, Zheng Z, Zhang M, Zhang T, Jin J, Zhang X, Yao G, Kong D, Zhang C (2022) Gut microbiome dysbiosis contributes to abdominal aortic aneurysm by promoting neutrophil extracellular trap formation. Cell Host Microbe 30(10):1450–1463. https://doi.org/10.1016/j.chom.2022.09.004

    Article  CAS  PubMed  Google Scholar 

  • Troletti CD, Enzmann G, Chiurchiù V, Kamermans A, Tietz SM, Norris PC, Jahromi NH, Leuti A, van der Pol SM, Schouten M (2021) Pro-resolving lipid mediator lipoxin A4 attenuates neuro-inflammation by modulating T cell responses and modifies the spinal cord lipidome. Cell Rep 35(9):109201

    Article  PubMed Central  Google Scholar 

  • Vafaei S, Taheri H, Hajimomeni Y, Fakhre Yaseri A, Abolhasani Zadeh F (2022) The role of NLRP3 inflammasome in colorectal cancer: Potential therapeutic target. Clin Transl Oncol 24(10):1881–1889

    Article  CAS  PubMed  Google Scholar 

  • Vassiliou EK, Kesler OM, Tadros JH, Ganea D (2008) Bone marrow-derived dendritic cells generated in the presence of resolvin E1 induce apoptosis of activated CD4+ T cells. J Immunol 181(7):4534–4544

    Article  CAS  PubMed  Google Scholar 

  • Wen Y, Zhang M, Yao Y, Gao Y, Zhang X, Lin Y, Cai X (2023) Biological regulation on synovial fibroblast and the treatment of rheumatoid arthritis by nobiletin-loaded tetrahedral framework nucleic acids cargo tank. Chin Chem Lett 34(2):107549

    Article  CAS  Google Scholar 

  • Weylandt K-H (2016) Docosapentaenoic acid derived metabolites and mediators–the new world of lipid mediator medicine in a nutshell. Eur J Pharmacol 785:108–115

    Article  CAS  PubMed  Google Scholar 

  • Xu H, Li L, Wang S, Wang Z, Qu L, Wang C, Xu K (2023) Royal jelly acid suppresses hepatocellular carcinoma tumorigenicity by inhibiting H3 histone lactylation at H3K9la and H3K14la sites. Phytomedicine. https://doi.org/10.1016/j.phymed.2023.154940

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu H, Van der Jeught K, Zhou Z, Zhang L, Yu T, Sun Y, Li Y, Wan C, So KM, Liu D (2021) Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation. J Clin Investig. https://doi.org/10.1172/JCI146832

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamada H, Saegusa J, Sendo S, Ueda Y, Okano T, Shinohara M, Morinobu A (2021) Effect of resolvin D5 on T cell differentiation and osteoclastogenesis analyzed by lipid mediator profiling in the experimental arthritis. Sci Rep 11(1):17312. https://doi.org/10.1038/s41598-021-96530-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zafari P, Yari K, Mostafaei S, Iranshahi N, Assar S, Fekri A, Taghadosi M (2018) Analysis of Helios gene expression and Foxp3 TSDR methylation in the newly diagnosed Rheumatoid Arthritis patients. Immunol Invest 47(6):632–642

    Article  CAS  PubMed  Google Scholar 

  • Zhang K, Liang F, Qaria MA, Wang H, Lin M, Zhang F (2022a) Roles of 630 nm red light-emitting diode in inhibition of RhoA signal transduction pathway via reducing PLEKHG5 expression and alleviation of inflammatory response in macrophages. J Biol Regul Homeost Agents 36(5):1419–1426

    CAS  Google Scholar 

  • Zhang K, Yang Y, Ge H, Wang J, Lei X, Chen X, Wan F, Feng H, Tan L (2022b) Neurogenesis and proliferation of neural stem/progenitor cells conferred by artesunate via FOXO3a/p27Kip1 Axis in mouse stroke model. Mol Neurobiol 59(8):4718–4729

    Article  CAS  PubMed  Google Scholar 

  • Zhao C, Gu Y, Zeng X, Wang J (2018) NLRP3 inflammasome regulates Th17 differentiation in rheumatoid arthritis. Clin Immunol 197:154–160

    Article  CAS  PubMed  Google Scholar 

  • Zhao J, Chen X, Ho K-H, Cai C, Li C-W, Yang M, Yi C (2021) Nanotechnology for diagnosis and therapy of rheumatoid arthritis: Evolution towards theranostic approaches. Chin Chem Lett 32(1):66–86

    Article  CAS  Google Scholar 

  • Zhu Y, Huang R, Wu Z, Song S, Cheng L, Zhu R (2021) Deep learning-based predictive identification of neural stem cell differentiation. Nat Commun 12(1):2614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Author information

Authors and Affiliations

  1. Department of Rheumatology, The Fourth Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, 150000, China

    Xiurong Zhang

  2. Department of Rheumatology, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, 150000, China

    Hongting Zhang

Authors
  1. Xiurong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongting Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HZ contributed to the idea design and literature search. XZ wrote parts of the manuscript and contributed to designing the figure.

Corresponding author

Correspondence to Hongting Zhang.

Ethics declarations

Conflict of interest

The authors have not disclosed any competing interests.

Consent for publication

All the authors agree and consent to the publication of this study.

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

Zhang, X., Zhang, H. Pro-resolving and anti-inflammatory effects of resolvins and protectins in rheumatoid arthritis. Inflammopharmacol 31, 2995–3004 (2023). https://doi.org/10.1007/s10787-023-01343-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-023-01343-5

Keywords

Search

Navigation