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.

The pyrin inflammasome aggravates inflammatory cell migration in patients with familial Mediterranean fever

Abstract

Background

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by pathogenic variants of the MEFV gene, which encodes pyrin. Leukocyte migration to serosal sites is a key event during inflammation in FMF. The pyrin inflammasome is a multiprotein complex involved in inflammation. Here, we aimed to determine the relationship between inflammatory cell migration and the pyrin inflammasome in FMF patients.

Methods

Monocytes were isolated from blood samples collected from patients with FMF, healthy controls, and a patient with cryopyrin-associated periodic syndrome (CAPS), which served as a disease control. Inflammasome proteins were analyzed under inflammasome activation and inhibition by western blotting. Cell migration assays were performed with the isolated primary monocytes as well as THP-1 monocytes and THP-1-derived macrophages.

Results

When the pyrin inflammasome was suppressed, migration of monocytes from FMF patients was significantly decreased compared to the migration of monocytes from the CAPS patient and healthy controls. Cell line experiments showed a relationship between pyrin inflammasome activation and cell migration.

Conclusions

These findings suggest that the increased cell migration in FMF is due to the presence of more active pyrin inflammasome. This study contributes to our understanding of the role of pyrin in inflammatory cell migration through inflammasome formation.

Impact

  • The pyrin inflammasome may play a role in inflammatory cell migration.

  • FMF patients show a pyrin inflammasome-dependent increase in inflammatory cell migration.

  • Correlations between the pyrin inflammasome and cell migration were observed in both THP-1 monocytes and THP-1-derived macrophages.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Expression analysis of inflammasome proteins.
Fig. 2: Determination of monocyte migration and IL-1β secretion.
Fig. 3: Comparison of inhibition of cell migration and IL-1β secretion in study group.
Fig. 4: Transwell experiments performed in THP-1 cells.
Fig. 5: Wound healing assay performed in THP-1-derived macrophages.

References

  1. 1.

    Hashkes, P. J., Laxer, R. M. & Simon, A. (Eds). Textbook of Autoinflammation (Springer International Publishing, 2019).

  2. 2.

    Samuels, J. & Ozen, S. Familial Mediterranean fever and the other autoinflammatory syndromes: evaluation of the patient with recurrent fever. Curr. Opin. Rheumatol. 18, 108–117 (2006).

    Article  Google Scholar 

  3. 3.

    Waite, A. L. et al. Pyrin and ASC co-localize to cellular sites that are rich in polymerizing actin. Exp. Biol. Med. 234, 40–52 (2009).

    CAS  Article  Google Scholar 

  4. 4.

    Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).

    CAS  Article  Google Scholar 

  5. 5.

    Waite, A. L. et al. Pyrin modulates the intracellular distribution of PSTPIP1. PLoS ONE 4, e6147 (2009).

    Article  Google Scholar 

  6. 6.

    Balci-Peynircioglu, B. et al. Potential role of pyrin, the protein mutated in familial Mediterranean fever, during inflammatory cell migration. Clin. Exp. Rheumatol. 36, 116–124 (2018).

    PubMed  Google Scholar 

  7. 7.

    Chae, J. J. et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. Immunity 34, 755–768 (2011).

    CAS  Article  Google Scholar 

  8. 8.

    Park, Y. H., Wood, G., Kastner, D. L. & Chae, J. J. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat. Immunol. 17, 914–921 (2016).

    CAS  Article  Google Scholar 

  9. 9.

    Magnotti, F. et al. Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients. EMBO Mol. Med. 11, e10547 (2019).

    CAS  Article  Google Scholar 

  10. 10.

    Sharma, D. et al. RIPK3 promotes Mefv expression and pyrin inflammasome activation via modulation of mTOR signaling. J. Immunol. https://doi.org/10.4049/jimmunol.2000244 (2020).

  11. 11.

    Sharma, D. et al. Pyrin inflammasome regulates tight junction integrity to restrict colitis and tumorigenesis. Gastroenterology 154, 948–964.e948 (2018).

    CAS  Article  Google Scholar 

  12. 12.

    Inoue, M., Williams, K. L., Gunn, M. D. & Shinohara, M. L. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 109, 10480–10485 (2012).

    CAS  Article  Google Scholar 

  13. 13.

    Wang, Y. et al. Activation of NLRP3 inflammasome enhances the proliferation and migration of A549 lung cancer cells. Oncol. Rep. 35, 2053–2064 (2016).

    CAS  Article  Google Scholar 

  14. 14.

    Yalçınkaya, F. et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology 48, 395–398 (2009).

    Article  Google Scholar 

  15. 15.

    Gattorno, M. et al. Classification criteria for autoinflammatory recurrent fevers. Ann. Rheum. Dis. 78, 1025–1032 (2019).

  16. 16.

    de Almeida, M. C., Silva, A. C., Barral, A., Barral & Netto, M. A simple method for human peripheral blood monocyte isolation. Mem. Inst. Oswaldo Cruz 95, 221–223 (2000).

    Article  Google Scholar 

  17. 17.

    Harapas, C. R., Steiner, A., Davidson, S. & Masters, S. L. An update on autoinflammatory diseases: inflammasomopathies. Curr. Rheumatol. Rep. 20, 40 (2018).

    Article  Google Scholar 

  18. 18.

    Akkaya-Ulum, Y. Z., Balci-Peynircioglu, B., Purali, N. & Yilmaz, E. Pyrin–PSTPIP1 colocalises at the leading edge during cell migration. Cell Biol. Int. 39, 1384–1394 (2015).

    CAS  Article  Google Scholar 

  19. 19.

    Akbaba, T. H. et al. Analysis of polymorphisms in the colchicine binding site of tubulin in colchicine-resistant familial Mediterranean fever patients. Mol. Biol. Rep. 47, 9005–9011 (2020).

    Article  Google Scholar 

  20. 20.

    Lemor, M., de Bustros, S. & Glaser, B. M. Low-dose colchicine inhibits astrocyte, fibroblast, and retinal pigment epithelial cell migration and proliferation. Arch. Ophthalmol. 104, 1223–1225 (1986).

    CAS  Article  Google Scholar 

  21. 21.

    Taskiran, E. Z. et al. The effect of colchicine on pyrin and pyrin interacting proteins. J. Cell. Biochem. 113, 3536–3546 (2012).

    CAS  Article  Google Scholar 

  22. 22.

    Akbaba, T. H., Sag, E., Balci-Peynircioglu, B. & Ozen, S. Epigenetics for clinicians from the perspective of pediatric rheumatic diseases. Curr. Rheumatol. Rep. 22, 46 (2020).

    CAS  Article  Google Scholar 

  23. 23.

    Balci-Peynircioglu, B., Akkaya-Ulum, Y. Z., Akbaba, T. H. & Tavukcuoglu, Z. Potential of miRNAs to predict and treat inflammation from the perspective of Familial Mediterranean fever. Inflamm. Res. 68, 905–913 (2019).

    CAS  Article  Google Scholar 

  24. 24.

    Felix, K. M., Tahsin, S. & Wu, H. J. Host-microbiota interplay in mediating immune disorders. Ann. NY Acad. Sci. 1417, 57–70 (2018).

    Article  Google Scholar 

  25. 25.

    Akbaba, T. H. & Balcı-Peynircioğlu, B. Potential impacts of gut microbiota on immune system related diseases: current studies and future challenges. Acta Med. 49, 31–37 (2018).

    Google Scholar 

Download references

Acknowledgements

We would like to give special thanks to J.J. Chae (National Institutes of Health, USA) for providing the pyrin antibody, arachidonic acid, and valuable advice during the project. This study was funded by Hacettepe University Scientific Research Projects Coordination Unit [grant number TYL-2018-17354].

Author information

Affiliations

Authors

Contributions

T.H.A., Z.Y.A.-U., and B.B.-P.: conceptualization; T.H.A.: investigation; T.H.A., S.D., and S.O.: resources; T.H.A.: writing the original draft; B.B.-P. and S.O.: writing the review and Editing; T.H.A., Z.Y.A.-U., and B.B.-P.: funding acquisition. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Banu Balci-Peynircioglu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Statement of consents

The study was approved by the Hacettepe University Non-interventional Clinical Researches Ethics Board (GO 17/514). Written consent was obtained from all parents and children.

Additional information

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Akbaba, T.H., Akkaya-Ulum, Y.Z., Demir, S. et al. The pyrin inflammasome aggravates inflammatory cell migration in patients with familial Mediterranean fever. Pediatr Res (2021). https://doi.org/10.1038/s41390-021-01559-7

Download citation

Search

Quick links