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.

  • Article
  • Published:

Ets-2 deletion in myeloid cells attenuates IL-1α-mediated inflammatory disease caused by a Ptpn6 point mutation

Cellular & Molecular Immunology volume 18, pages 1798–1808 (2021)Cite this article

Subjects

Abstract

The SHP-1 protein encoded by the Ptpn6 gene has been extensively studied in hematopoietic cells in the context of inflammation. A point mutation in this gene (Ptpn6spin) causes spontaneous inflammation in mice, which has a striking similarity to neutrophilic dermatoses in humans. Recent findings highlighted the role of signaling adapters and kinases in promoting inflammation in Ptpn6spin mice; however, the underlying transcriptional regulation is poorly understood. Here, we report that SYK is important for driving neutrophil infiltration and initiating wound healing responses in Ptpn6spin mice. Moreover, we found that deletion of the transcription factor Ets2 in myeloid cells ameliorates cutaneous inflammatory disease in Ptpn6spin mice through transcriptional regulation of its target inflammatory genes. Furthermore, Ets-2 drives IL-1α-mediated inflammatory signaling in neutrophils of Ptpn6spin mice. Overall, in addition to its well-known role in driving inflammation in cancer, Ets-2 plays a major role in regulating IL-1α-driven Ptpn6spin-mediated neutrophilic dermatoses.

Model for the role of ETS-2 in neutrophilic inflammation in Ptpn6spin mice. Mutation of the Ptpn6 gene results in SYK phosphorylation which then sequentially activates MAPK signaling pathways and activation of ETS-2. This leads to activation of ETS-2 target genes that contribute to neutrophil migration and inflammation. When Ets2 is deleted in Ptpn6spin mice, the expression of these target genes is reduced, leading to the reduced pathology in neutrophilic dermatoses.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Cohen, P. R. Neutrophilic dermatoses: a review of current treatment options. Am. J. Clin. Dermatol. 10, 301–312 (2009).

    PubMed  Google Scholar 

  2. Callen, J. P. Neutrophilic dermatoses. Dermatol. Clin. 20, 409–419 (2002).

    PubMed  Google Scholar 

  3. Nesterovitch, A. B. et al. Alteration in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6/SHP1) may contribute to neutrophilic dermatoses. Am. J. Pathol. 178, 1434–1441 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Eriksen, K. W. et al. Deficient SOCS3 and SHP-1 expression in psoriatic T cells. J. Invest. Dermatol. 130, 1590–1597 (2010).

    CAS  PubMed  Google Scholar 

  5. Christophi, G. P. et al. Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype. Lab. Invest. 89, 742–759 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhu, Z. et al. Tyrosine phosphatase SHP-1 in allergic and anaphylactic inflammation. Immunol. Res. 47, 3–13 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Green, M. C. & Shultz, L. D. Motheaten, an immunodeficient mutant of the mouse. I. Genetics and pathology. J. Hered. 66, 250–258 (1975).

    CAS  PubMed  Google Scholar 

  8. Tsui, H. W., Siminovitch, K. A., de Souza, L. & Tsui, F. W. Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat. Genet. 4, 124–129 (1993).

    CAS  PubMed  Google Scholar 

  9. Nesterovitch, A. B. et al. Spontaneous insertion of a b2 element in the ptpn6 gene drives a systemic autoinflammatory disease in mice resembling neutrophilic dermatosis in humans. Am. J. Pathol. 178, 1701–1714 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Croker, B. A. et al. Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger. Proc. Natl Acad. Sci. USA 105, 15028–15033 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Pao, L. I., Badour, K., Siminovitch, K. A. & Neel, B. G. Nonreceptor protein-tyrosine phosphatases in immune cell signaling. Annu Rev. Immunol. 25, 473–523 (2007).

    CAS  PubMed  Google Scholar 

  12. Gurung, P. et al. Tyrosine kinase SYK licenses MyD88 adaptor protein to instigate IL-1alpha-mediated inflammatory disease. Immunity 46, 635–648 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lukens, J. R. et al. RIP1-driven autoinflammation targets IL-1alpha independently of inflammasomes and RIP3. Nature 498, 224–227 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Tartey, S., Gurung, P., Dasari, T. K., Burton, A. & Kanneganti, T. D. ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis. J. Clin. Invest. 128, 2042–2047 (2018).

    PubMed  PubMed Central  Google Scholar 

  15. Tartey, S., Gurung, P., Samir, P., Burton, A. & Kanneganti, T. D. Cutting Edge: dysregulated CARD9 signaling in neutrophils drives inflammation in a mouse model of neutrophilic dermatoses. J. Immunol. 201, 1639–1644 (2018).

    CAS  PubMed  Google Scholar 

  16. Abram, C. L., Roberge, G. L., Pao, L. I., Neel, B. G. & Lowell, C. A. Distinct roles for neutrophils and dendritic cells in inflammation and autoimmunity in motheaten mice. Immunity 38, 489–501 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Mocsai, A., Ruland, J. & Tybulewicz, V. L. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol. 10, 387–402 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mocsai, A., Zhou, M., Meng, F., Tybulewicz, V. L. & Lowell, C. A. Syk is required for integrin signaling in neutrophils. Immunity 16, 547–558 (2002).

    CAS  PubMed  Google Scholar 

  19. Mocsai, A. et al. G-protein-coupled receptor signaling in Syk-deficient neutrophils and mast cells. Blood 101, 4155–4163 (2003).

    CAS  PubMed  Google Scholar 

  20. Zhong, X., Chen, B., Yang, L. & Yang, Z. Molecular and physiological roles of the adaptor protein CARD9 in immunity. Cell Death Dis. 9, 52 (2018).

    PubMed  PubMed Central  Google Scholar 

  21. Roth, S. & Ruland, J. Caspase recruitment domain-containing protein 9 signaling in innate immunity and inflammation. Trends Immunol. 34, 243–250 (2013).

    CAS  PubMed  Google Scholar 

  22. Ghosh, D., Tsokos, G. C. & Kyttaris, V. C. c-Jun and Ets2 proteins regulate expression of spleen tyrosine kinase in T cells. J. Biol. Chem. 287, 11833–11841 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Krishnan, S. et al. Differential expression and molecular associations of Syk in systemic lupus erythematosus T cells. J. Immunol. 181, 8145–8152 (2008).

    CAS  PubMed  Google Scholar 

  24. Wei, G. et al. Activated Ets2 is required for persistent inflammatory responses in the motheaten viable model. J. Immunol. 173, 1374–1379 (2004).

    CAS  PubMed  Google Scholar 

  25. Tecchio, C., Micheletti, A. & Cassatella, M. A. Neutrophil-derived cytokines: facts beyond expression. Front. Immunol. 5, 508 (2014).

    PubMed  PubMed Central  Google Scholar 

  26. Di Paolo, N. C. & Shayakhmetov, D. M. Interleukin 1alpha and the inflammatory process. Nat. Immunol. 17, 906–913 (2016).

    PubMed  PubMed Central  Google Scholar 

  27. Rider, P. et al. IL-1alpha and IL-1beta recruit different myeloid cells and promote different stages of sterile inflammation. J. Immunol. 187, 4835–4843 (2011).

    CAS  PubMed  Google Scholar 

  28. Quinn, S. R. et al. The role of Ets2 transcription factor in the induction of microRNA-155 (miR-155) by lipopolysaccharide and its targeting by interleukin-10. J. Biol. Chem. 289, 4316–4325 (2014).

    CAS  PubMed  Google Scholar 

  29. Tonks, N. K. Protein tyrosine phosphatases: from genes, to function, to disease. Nat. Rev. Mol. Cell Biol. 7, 833–846 (2006).

    CAS  PubMed  Google Scholar 

  30. Cao, H. & Hegele, R. A. Identification of polymorphisms in the human SHP1 gene. J. Hum. Genet. 47, 445–447 (2002).

    CAS  PubMed  Google Scholar 

  31. Christophi, G. P. et al. SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients. Lab. Invest. 88, 243–255 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Dubois, M. J. et al. The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis. Nat. Med. 12, 549–556 (2006).

    CAS  PubMed  Google Scholar 

  33. Geraldes, P. et al. Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat. Med. 15, 1298–1306 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Robinson, M. J. et al. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. J. Exp. Med. 206, 2037–2051 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Gringhuis, S. I. et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk. Nat. Immunol. 10, 203–213 (2009).

    CAS  PubMed  Google Scholar 

  36. Yamada, T. et al. IL-1 induced chemokine production through the association of Syk with TNF receptor-associated factor-6 in nasal fibroblast lines. J. Immunol. 167, 283–288 (2001).

    CAS  PubMed  Google Scholar 

  37. Baran, C. P. et al. Transcription factor ets-2 plays an important role in the pathogenesis of pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 45, 999–1006 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Trojanowska, M. Ets factors and regulation of the extracellular matrix. Oncogene 19, 6464–6471 (2000).

    CAS  PubMed  Google Scholar 

  39. Yang, H. et al. ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas. Elife 4, e10870 (2015).

    PubMed  PubMed Central  Google Scholar 

  40. Sementchenko, V. I. & Watson, D. K. Ets target genes: past, present and future. Oncogene 19, 6533–6548 (2000).

    CAS  PubMed  Google Scholar 

  41. Yamamoto, H. et al. Defective trophoblast function in mice with a targeted mutation of Ets2. Genes Dev. 12, 1315–1326 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Saijo, K. et al. Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development. Nat. Immunol. 4, 274–279 (2003).

    CAS  PubMed  Google Scholar 

  43. Pao, L. I. et al. B cell-specific deletion of protein-tyrosine phosphatase Shp1 promotes B-1a cell development and causes systemic autoimmunity. Immunity 27, 35–48 (2007).

    CAS  PubMed  Google Scholar 

  44. Clausen, B. E., Burkhardt, C., Reith, W., Renkawitz, R. & Forster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8, 265–277 (1999).

    CAS  PubMed  Google Scholar 

  45. Passegue, E., Wagner, E. F. & Weissman, I. L. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119, 431–443 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr. Yury Miller for the Sykfl/fl mice and Dr. Bruce Beutler for the Ptpn6 mutant mice. We would like to thank the members of the Kanneganti lab for their comments and suggestions and Rebecca Tweedell, PhD, for scientific editing. This work was supported by the K22 NIAID Career Transition Award AI127836 to P.G., the National Institutes of Health grants CA163507, AR056296, AI124346 and AI101935 and by the American Lebanese Syrian Associated Charities to T.-D.K.

Author information

Authors and Affiliations

  1. Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Sarang Tartey, Prajwal Gurung, Rajendra Karki, Amanda Burton & Thirumala-Devi Kanneganti

  2. Inflammation Program, University of Iowa, Iowa City, IA, 52241, USA

    Prajwal Gurung

  3. Centre for Innate Immunity & Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, 3168, Australia

    Paul Hertzog

Authors
  1. Sarang Tartey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prajwal Gurung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rajendra Karki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amanda Burton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul Hertzog
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thirumala-Devi Kanneganti
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.T. and T.-D.K. conceptualized the study; S.T. designed the experiments; S.T., P.G., R.K. and A.B. performed the experiments; P.H. provided Ets2fl/fl mice; and S.T. analyzed the data and wrote the paper. All authors critically evaluated and edited the paper and approved the final version. T.-D.K. oversaw the project.

Corresponding author

Correspondence to Thirumala-Devi Kanneganti.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tartey, S., Gurung, P., Karki, R. et al. Ets-2 deletion in myeloid cells attenuates IL-1α-mediated inflammatory disease caused by a Ptpn6 point mutation. Cell Mol Immunol 18, 1798–1808 (2021). https://doi.org/10.1038/s41423-020-0398-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-0398-7

Keywords

This article is cited by

Search

Advanced search

Quick links