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Towards a pro-resolving concept in systemic lupus erythematosus

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Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with prominent chronic inflammatory aspects. SLE most often affects women (9:1) in childbearing age. The multifactorial nature of the etiopathogenesis of SLE involves a deficient clearance of dead and dying cells. This is supported by the occurrence of autoantibodies directed against autoantigens modified in dying and dead cells (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12) that are deposited in various tissues, including skin, kidneys, joints, muscles, and brain. The subsequent hyperinflammatory response often leads to irreparable tissue damage and organ destruction. In healthy individuals, dead and dying cells are rapidly removed by macrophages in an anti-inflammatory manner, referred to as efferocytosis. In SLE, extensive and prolonged cell death (apoptosis, necrosis, neutrophil extracellular trap (NET) formation) leads to autoantigens leaking out of the not cleared cell debris. These neo-epitopes are subsequently presented to B cells by follicular dendritic cells in the germinal centers of secondary lymphoid tissues conditioning the break of self-tolerance. Activation of autoreactive B cells and subsequent production of autoantibodies facilitate the formation of immune complexes (ICs) fueling the inflammatory response and leading to further tissue damage. ICs may also be ingested by phagocytes, which then produce further pro-inflammatory cytokines. These processes establish a vicious circle that leads to sustained inflammation. This review highlights the cell death–related events in SLE, the protagonists involved in SLE pathogenesis, the resolution of inflammation in various tissues affected in SLE, and explores strategies for intervention to restore hemostasis in a hyperinflammatory state.

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Funding

This study is supported by the Deutsche Forschungsgemeinschaft (DFG) and Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) within the funding program Open Access Publishing. This work was partially supported by the German Research Foundation (DFG) to MH (CRC1181-C03, KFO257) by the Volkswagen-Stiftung grant no. 90361 to MH and by the doctoral training program GK1660 of the DFG to JK.

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Authors and Affiliations

  1. Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany

    Sebastian Boeltz, Melanie Hagen, Jasmin Knopf, Aparna Mahajan, Maximilian Schick, Yi Zhao, Jürgen Rech, Luis E. Muñoz & Martin Herrmann

  2. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China

    Yi Zhao

  3. Department of Dermatology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Cornelia Erfurt-Berge

  4. Department of Internal Medicine 3, Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany

    Luis E. Muñoz

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  1. Sebastian Boeltz
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Boeltz, S., Hagen, M., Knopf, J. et al. Towards a pro-resolving concept in systemic lupus erythematosus. Semin Immunopathol 41, 681–697 (2019). https://doi.org/10.1007/s00281-019-00760-5

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