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A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation

Nature Genetics volume 56, pages 85–99 (2024)Cite this article

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Abstract

Inflammation is characterized by a biphasic cycle consisting initially of a proinflammatory phase that is subsequently resolved by anti-inflammatory processes. Interleukin-1β (IL-1β) is a master regulator of proinflammation and is encoded within the same topologically associating domain (TAD) as IL-37, which is an anti-inflammatory cytokine that opposes the function of IL-1β. Within this TAD, we identified a long noncoding RNA called AMANZI, which negatively regulates IL-1β expression and trained immunity through the induction of IL37 transcription. We found that the activation of IL37 occurs through the formation of a dynamic long-range chromatin contact that leads to the temporal delay of anti-inflammatory responses. The common variant rs16944 present in AMANZI augments this regulatory circuit, predisposing individuals to enhanced proinflammation or immunosuppression. Our work illuminates a chromatin-mediated biphasic circuit coordinating expression of IL-1β and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD.

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Fig. 1: The rs16944 SNP alters the expression of IL1B and AMANZI and affects induction of trained immunity and tolerance.
Fig. 2: AMANZI is a nuclear-resident, cis-acting lncRNA that negatively regulates IL1B transcription.
Fig. 3: IL1B and IL37 transcription is controlled by a biphasic circuit that is activated by IL-1β eRNA and regulated by AMANZI.
Fig. 4: AMANZI mediates a long-range chromatin loop with IL37 to activate its transcription.
Fig. 5: AMANZI regulates IL-1β expression in a SMAD3-dependent manner via IL-1β eRNA.
Fig. 6: The SNP rs16944 affects AMANZI stability by differentially binding to YTH proteins.
Fig. 7: AMANZI A modulates trained immunity by controlling IL37 expression.
Fig. 8: A biphasic circuit regulates IL-1β and IL-37 expression to coordinate pro- and anti-inflammatory processes from within a single TAD.

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Data availability

The data that support the findings of the present study are available from the corresponding author upon reasonable request. RNA-seq data are available in the Gene Expression Omnibus under accession no. GSE244833. Proteomics data are available in the PRIDE database under accession no. PXD045971.

Code availability

No code was generated in the present study.

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Acknowledgements

We thank all members of the Epigenomics & Single Cell Biophysics Group (Mhlanga laboratory) and all members of the laboratories of M.G.N., L.A.B.J. and P.S. We thank INTRIM consortium members for comments on the paper. We thank R. Weinlich for contributing reagents and participants to the present study and G. B. Olivato and F. B. Hohmann for ICU patients’ data collection. We thank all volunteers in the 200FG cohort. The Vermeulen laboratory is part of the Oncode Institute, which is partly funded by the Dutch Cancer Society.

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Author notes

  1. Ezio T. Fok

    Present address: Lemba Therapeutics, Nijmegen, the Netherlands

Authors and Affiliations

  1. Department of Cell Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands

    Ezio T. Fok, Yutaka Negishi & Musa M. Mhlanga

  2. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands

    Ezio T. Fok, Yutaka Negishi & Musa M. Mhlanga

  3. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands

    Simone J. C. F. M. Moorlag, Laszlo A. Groh, Jéssica Cristina dos Santos, Leo A. B. Joosten & Mihai G. Netea

  4. Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University, Nijmegen, the Netherlands

    Cathrin Gräwe & Michiel Vermeulen

  5. Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, Brazil

    David Pablo da Cunha Jolvino, Letícia Busato Migliorini & Patricia Severino

  6. Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia

    David Pablo da Cunha Jolvino

  7. Department of Critical Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil

    Ary Serpa Neto

  8. Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands

    Michiel Vermeulen

  9. Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Leo A. B. Joosten

  10. Lemba Therapeutics, Nijmegen, the Netherlands

    Valerie Villacorta Monge, Daphne D. D. Craenmehr, Mellanie van Roosmalen & Stephanie Fanucchi

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Contributions

E.T.F., S.F., M.G.N. and M.M.M. designed the study. E.T.F. and S.J.C.F.M.M. performed most experiments and collected and analyzed data. S.J.C.F.M.M., L.A.G. and J.C.d.S. performed the experiments on healthy human-derived monocytes. D.P.d.C.J., L.B.M., A.S.N. and P.S. performed the experiments on whole blood from patients with sepsis and septic shock. Y.N. carried out data analysis. V.V.M., D.D.D.C. and M.v.R. conducted experiments and analyzed data. E.T.F., S.J.C.F.M.M., S.F., L.A.B.J., P.S., M.G.N. and M.M.M. discussed and edited the paper. E.T.F., S.F. and M.M.M. co-wrote the paper. M.M.M. designed experiments, analyzed data and supervised the study.

Corresponding author

Correspondence to Musa M. Mhlanga.

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Competing interests

M.M.M. and S.F. are founders of Lemba Therapeutics. M.G.N. and L.A.B.J. are founders of TTxD. M.M.M., S.F., M.G.N. and L.A.B.J. are equity holders in Lemba Therapeutics. The other authors declare no competing interests.

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Supplementary Table 1

RNA-seq count table.

Supplementary Table 2

Proteomics table showing significant hits.

Supplementary Table 3

Reagents and materials.

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Fok, E.T., Moorlag, S.J.C.F.M., Negishi, Y. et al. A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation. Nat Genet 56, 85–99 (2024). https://doi.org/10.1038/s41588-023-01598-2

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