Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

A novel mechanism of EAE resistance highlights the conflicting roles of progranulin-mediated immunosuppression and antigen processing

Cellular & Molecular Immunology volume 18, pages 506–507 (2021)Cite this article

Subjects

Progranulin (PGRN) is a secreted growth-factor-like molecule with multiple biological functions; elevated PGRN expression correlates with the activity of various autoimmune diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE).1,2,3,4 PGRN deficiency is associated with an enhanced inflammatory response and commonly results in increased susceptibility to the onset and progression of various autoimmune conditions in murine models, including inflammatory arthritis,4 inflammatory bowel diseases,5 and inflammatory skin diseases.6 In contrast, PGRN expression has been shown to aggravate some autoimmune conditions, including lupus nephritis.3

In a recent study published in Cellular and Molecular Immunology, Schmitz and colleagues reported that patients with multiple sclerosis (MS) recapitulate the familiar incidence of elevated levels of circulating PGRN in autoimmune conditions.10 Somewhat surprisingly, given PGRN’s well-established neuroprotective activity, PGRN-deficient mice (PGRN−/−) exhibited resistance to the experimental autoimmune encephalomyelitis (EAE) model of MS. PGRN deficiency-associated resistance to EAE was lost upon bone marrow transplantation from mice overexpressing PGRN in myeloid cells (LysM-Grn-OE) or wild-type donors. Interestingly, LysM-Grn-OE mice exhibited a mild resistance to EAE, and reduction of PGRN levels through administration of a monoclonal anti-PGRN antibody resulted in exacerbation of clinical EAE scores in LysM-Grn-OE and wild-type mice. These initial observations led Schmitz et al. to postulate that PGRN exerts its well-documented anti-inflammatory effects in EAE but is required for the initiation of the disease model.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Jian, J., Li, G., Hettinghouse, A. & Liu, C. Progranulin: a key player in autoimmune diseases. Cytokine 101, 48–55 (2018).

    Article  CAS  Google Scholar 

  2. Cui, Y., Hettinghouse, A. & Liu, C. J. Progranulin: a conductor of receptors orchestra, a chaperone of lysosomal enzymes and a therapeutic target for multiple diseases. Cytokine Growth Factor Rev. 45, 53–64 (2019).

    Article  CAS  Google Scholar 

  3. Chen, X., Wen, Z., Xu, W. & Xiong, S. Granulin exacerbates lupus nephritis via enhancing macrophage M2b polarization. PLoS ONE 8, e65542 (2013).

    Article  CAS  Google Scholar 

  4. Tang, W. et al. The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332, 478–484 (2011).

    Article  CAS  Google Scholar 

  5. Wei, F. et al. PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner. Sci. Rep. 4, 7023 (2014).

    Article  CAS  Google Scholar 

  6. Zhao, Y. P., Tian, Q. Y. & Liu, C. J. Progranulin deficiency exaggerates, whereas progranulin-derived Atsttrin attenuates, severity of dermatitis in mice. FEBS Lett. 587, 1805–1810 (2013).

    Article  CAS  Google Scholar 

  7. Lata, M., Hettinghouse, A. S. & Liu, C. J. Targeting tumor necrosis factor receptors in ankylosing spondylitis. Ann. NY Acad. Sci. 1442, 5–16 (2019).

    Article  Google Scholar 

  8. Fu, W. et al. Foxo4- and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis. FASEB J. 31, 1354–1367 (2017).

    Article  CAS  Google Scholar 

  9. Wei, F., Zhang, Y., Zhao, W., Yu, X. & Liu, C. J. Progranulin facilitates conversion and function of regulatory T cells under inflammatory conditions. PLoS ONE 9, e112110 (2014).

    Article  Google Scholar 

  10. Schmitz K. et al. Progranulin deficiency confers resistance to autoimmune encephalomyelitis in mice. Cell. Mol. Immunol. (2019). https://doi.org/10.1038/s41423-019-0274-5. [Epub ahead of print].

Download references

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA

    Aubryanna Hettinghouse, Guanmin Gao & Chuan-ju Liu

  2. Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA

    Chuan-ju Liu

Authors
  1. Aubryanna Hettinghouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guanmin Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chuan-ju Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chuan-ju Liu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hettinghouse, A., Gao, G. & Liu, Cj. A novel mechanism of EAE resistance highlights the conflicting roles of progranulin-mediated immunosuppression and antigen processing. Cell Mol Immunol 18, 506–507 (2021). https://doi.org/10.1038/s41423-019-0292-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-019-0292-3

Search

Advanced search

Quick links