Skip to main content

Advertisement

SpringerLink
Log in

SHP2: its association and roles in systemic lupus erythematosus

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease. Src homology 2 domain containing protein tyrosine phosphatase (SHP2) is a member of the protein tyrosine phosphatases (PTPs) family. To date, relationship between SHP2 and SLE pathogenesis is not elucidated.

Method

We measured plasma levels of SHP2 in 328 SLE patients, 78 RA patients, 80 SS patients and 79 healthy controls by ELISA, and discussed association of SHP2 in SLE patients, potential of plasma SHP2 as a SLE biomarker. Moreover, histological and serological changes were evaluated by flow cytometry, HE/Masson examination, immunofluorescence test in pristane-induced lupus mice after SHP2 inhibitor injection to reveal role of SHP2 in lupus development.

Results

Results indicated that SHP2 plasma levels were upregulated in SLE patients and correlated with some clinical, laboratory characteristics such as proteinuria, pyuria, and may be a potential biomarker for SLE. After SHP2 inhibitor treatment, hepatosplenomegaly and histological severity of the kidney in lupus mice were improved. SHP2 inhibitor reversed DCs, Th1, and Th17 cells differentiation and downregulated inflammatory cytokines (IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF-α) and autoantibodies (ANA, anti-dsDNA) production in pristane-lupus mice.

Conclusion

In summary, SHP2 correlated with SLE pathogenesis and promoted the development of lupus.

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability statement

Data are available from the corresponding author on reasonable request.

References

  1. Yang C, et al. Increased levels of sirtuin-1 in systemic lupus erythematosus. Int J Rheum Dis. 2022;25(8):869–76.

    Article  CAS  PubMed  Google Scholar 

  2. Ci W, et al. Characteristics and risk factors of severe coronary artery disease in systemic lupus erythematosus: a multicenter, Chinese Rheumatism Date Center database study. Int J Rheum Dis. 2022;25(10):1186–95.

    Article  CAS  PubMed  Google Scholar 

  3. Chen Y. Systemic lupus erythematosus increases risk of incident atrial fibrillation: a systematic review and meta-analysis. Int J Rheum Dis. 2022;25(10):1097–106.

    Article  PubMed  Google Scholar 

  4. Sakata K, et al. Up-regulation of TLR7-mediated IFN-α production by plasmacytoid dendritic cells in patients with systemic lupus erythematosus. Front Immunol. 2018;9:1957.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ravetch JV, Bolland S. IgG Fc receptors. Annu Rev Immunol. 2001;19:275–90.

    Article  CAS  PubMed  Google Scholar 

  6. Axtell RC, Raman C, Steinman L. Type I interferons: beneficial in Th1 and detrimental in Th17 autoimmunity. Clin Rev Allergy Immunol. 2013;44(2):114–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Foster MH. T cells and B cells in lupus nephritis. Semin Nephrol. 2007;27(1):47–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Qu CK. The SHP-2 tyrosine phosphatase: signaling mechanisms and biological functions. Cell Res. 2000;10(4):279–88.

    Article  CAS  PubMed  Google Scholar 

  9. Hof P, et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998;92(4):441–50.

    Article  CAS  PubMed  Google Scholar 

  10. Barford D, Neel BG. Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2. Structure. 1998;6(3):249–54.

    Article  CAS  PubMed  Google Scholar 

  11. Frankson R, et al. Therapeutic targeting of oncogenic tyrosine phosphatases. Cancer Res. 2017;77(21):5701–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hsu MF, et al. Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria. Sci Rep. 2017;7(1):461.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Weißenberg SY, et al. Identification and characterization of post-activated B cells in systemic autoimmune diseases. Front Immunol. 2019;10:2136.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wang J, et al. Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus. J Clin Invest. 2016;126(6):2077–92.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Doria A, et al. Long-term prognosis and causes of death in systemic lupus erythematosus. Am J Med. 2006;119(8):700–6.

    Article  PubMed  Google Scholar 

  16. Carter EE, Barr SG, Clarke AE. The global burden of SLE: prevalence, health disparities and socioeconomic impact. Nat Rev Rheumatol. 2016;12(10):605–20.

    Article  PubMed  Google Scholar 

  17. Xiao P, et al. Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10. J Exp Med. 2019;216(2):337–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ganesan R, Rasool M. Interleukin 17 regulates SHP-2 and IL-17RA/STAT-3 dependent Cyr 61, IL-23 and GM-CSF expression and RANKL mediated osteoclastogenesis by fibroblast-like synoviocytes in rheumatoid arthritis. Mol Immunol. 2017;91:134–44.

    Article  CAS  PubMed  Google Scholar 

  19. Teng JF, et al. Lentivirus-mediated silencing of Src homology 2 domain-containing protein tyrosine phosphatase 2 inhibits release of inflammatory cytokines and apoptosis in renal tubular epithelial cells via inhibition of the TLR4/NF-kB pathway in renal ischemia-reperfusion injury. Kidney Blood Press Res. 2018;43(4):1084–103.

    Article  CAS  PubMed  Google Scholar 

  20. Lisbona MP, et al. Noonan syndrome associated with systemic lupus erythematosus. Lupus. 2009;18(3):267–9.

    Article  CAS  PubMed  Google Scholar 

  21. Leventopoulos G, et al. Noonan syndrome and systemic lupus erythematosus in a patient with a novel KRAS mutation. Clin Exp Rheumatol. 2010;28(4):556–7.

    CAS  PubMed  Google Scholar 

  22. Lopez-Rangel E, et al. Systemic lupus erythematosus and other autoimmune disorders in children with Noonan syndrome. Am J Med Genet A. 2005;139(3):239–42.

    Article  PubMed  Google Scholar 

  23. Alanay Y, Balcı S, Ozen S. Noonan syndrome and systemic lupus erythematosus: presentation in childhood. Clin Dysmorphol. 2004;13(3):161–3.

    Article  PubMed  Google Scholar 

  24. Amoroso A, et al. The unusual association of three autoimmune diseases in a patient with Noonan syndrome. J Adolesc Health. 2003;32(1):94–7.

    Article  PubMed  Google Scholar 

  25. Cheng Y, et al. Endogenous miR-204 protects the kidney against chronic injury in hypertension and diabetes. J Am Soc Nephrol. 2020;31(7):1539–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jiang J, et al. SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model. Mol Med. 2020;26(1):89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kuroda N, et al. Differential expression of SHP2, a protein-tyrosine phosphatase with SRC homology-2 domains, in various types of renal tumour. Virchows Arch. 1998;433(4):331–9.

    Article  CAS  PubMed  Google Scholar 

  28. Sorenson CM, Sheibani N. Altered regulation of SHP-2 and PTP 1B tyrosine phosphatases in cystic kidneys from bcl-2−/− mice. Am J Physiol Renal Physiol. 2002;282(3):F442–50.

    Article  CAS  PubMed  Google Scholar 

  29. Tseng CC, et al. α-Actinin-4 recruits Shp2 into focal adhesions to potentiate ROCK2 activation in podocytes. Life Sci Alliance. 2022;5(11):e202201557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li J, et al. PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment. Cancer Res. 2015;75(3):508–18.

    Article  CAS  PubMed  Google Scholar 

  31. Salmond RJ, et al. The src homology 2 domain-containing tyrosine phosphatase 2 regulates primary T-dependent immune responses and Th cell differentiation. J Immunol. 2005;175(10):6498–508.

    Article  CAS  PubMed  Google Scholar 

  32. Wang M, et al. SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis. iScience. 2022;25(4):104009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Frearson JA, Alexander DR. The phosphotyrosine phosphatase SHP-2 participates in a multimeric signaling complex and regulates T cell receptor (TCR) coupling to the Ras/mitogen-activated protein kinase (MAPK) pathway in Jurkat T cells. J Exp Med. 1998;187(9):1417–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nguyen TV, et al. Conditional deletion of Shp2 tyrosine phosphatase in thymocytes suppresses both pre-TCR and TCR signals. J Immunol. 2006;177(9):5990–6.

    Article  CAS  PubMed  Google Scholar 

  35. Luo Q, et al. Blocking initial infiltration of pioneer CD8(+) T cells into the CNS via inhibition of SHP-2 ameliorates experimental autoimmune encephalomyelitis in mice. Br J Pharmacol. 2014;171(7):1706–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xu Y, et al. Tyrosine phosphatase Shp2 regulates p115RhoGEF/Rho-dependent dendritic cell migration. Cell Mol Immunol. 2021;18(3):755–7.

    Article  CAS  PubMed  Google Scholar 

  37. Clark DN, et al. Cytokine inhibition as a strategy for treating systemic lupus erythematosus. Clin Immunol. 2013;148(3):335–43.

    Article  CAS  PubMed  Google Scholar 

  38. Jacob N, Stohl W. Cytokine disturbances in systemic lupus erythematosus. Arthritis Res Ther. 2011;13(4):228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bixler SL, et al. Suppressed Th17 levels correlate with elevated PIAS3, SHP2, and SOCS3 expression in CD4 T cells during acute simian immunodeficiency virus infection. J Virol. 2013;87(12):7093–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Barber DF, et al. PI3Kgamma inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nat Med. 2005;11(9):933–5.

    Article  CAS  PubMed  Google Scholar 

  41. Stanford SM, Bottini N. Targeting tyrosine phosphatases: time to end the stigma. Trends Pharmacol Sci. 2017;38(6):524–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Regen F, et al. Clozapine-induced agranulocytosis: evidence for an immune-mediated mechanism from a patient-specific in-vitro approach. Toxicol Appl Pharmacol. 2017;316:10–6.

    Article  CAS  PubMed  Google Scholar 

  43. Fizazi K, et al. Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol. 2009;27(15):2429–35.

    Article  CAS  PubMed  Google Scholar 

  44. Liu Q, et al. SH2 domain-containing phosphatase 2 inhibition attenuates osteoarthritis by maintaining homeostasis of cartilage metabolism via the docking protein 1/uridine phosphorylase 1/uridine cascade. Arthritis Rheumatol. 2022;74(3):462–74.

    Article  CAS  PubMed  Google Scholar 

  45. Wang J, et al. Therapeutic effect of the injectable thermosensitive hydrogel loaded with SHP099 on intervertebral disc degeneration. Life Sci. 2021;266: 118891.

    Article  CAS  PubMed  Google Scholar 

  46. Wang M, et al. Discovery of SHP2-D26 as a first, potent, and effective PROTAC degrader of SHP2 protein. J Med Chem. 2020;63(14):7510–28.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81701606).

Author information

Author notes

  1. Chan Yang, Rong Li and Lin-Chong Su contributed equally to this paper.

Authors and Affiliations

  1. Department of Evidence-Based Medicine, Southwest Medical University, 1 Xianglin Road, Luzhou, 646000, Sichuan, China

    Chan Yang, Rong Li & Wang-Dong Xu

  2. Department of Rheumatology and Immunology, Minda Hospital of Hubei Minzu University, 2 Wufengshan Road, Enshi, 445000, Hubei, China

    Lin-Chong Su

  3. Department of Rheumatology and Immunology, Affiliated Hospital of Southwest Medical University, 25 Taiping Road, Luzhou, 646000, Sichuan, China

    You-Yu Lan & An-Fang Huang

  4. Department of Laboratory Medicine, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China

    You-Qiang Wang

Authors
  1. Chan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin-Chong Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. You-Yu Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. You-Qiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wang-Dong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. An-Fang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study conception and design: CY, RL, LCS, WDX, AFH. Acquisition of data: YYL, YQW. Analysis and interpretation of data: CY, RL, LCS, WDX, AFH, YYL, YQW. Drafting the article: CY, RL, LCS, WDX, AFH. Final approval of the version of the article to be published: all authors, and that all authors agree to be accountable for all aspects of the work.

Corresponding authors

Correspondence to Wang-Dong Xu or An-Fang Huang.

Ethics declarations

Conflict of interest

All authors declare no conflicts of interest.

Ethical approval

All procedures were in accordance with the Ethics Research Committee of Affiliated Hospital of Southwest Medical University and the Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University under the Helsinki Declaration of 1975, as revised in 2000. Animal experiment procedures were approved by the Animal Ethics Committee of Southwest Medical University.

Informed consent

Informed consent was obtained from all participants.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 15 KB)

Supplementary file2 (DOCX 13 KB)

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

Yang, C., Li, R., Su, LC. et al. SHP2: its association and roles in systemic lupus erythematosus. Inflamm. Res. 72, 1501–1512 (2023). https://doi.org/10.1007/s00011-023-01760-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-023-01760-w

Keywords

Search

Navigation