Towards a pro-resolving concept in systemic lupus erythematosus

  • Sebastian Boeltz
  • Melanie Hagen
  • Jasmin Knopf
  • Aparna Mahajan
  • Maximilian Schick
  • Yi Zhao
  • Cornelia Erfurt-Berge
  • Jürgen Rech
  • Luis E. MuñozEmail author
  • Martin Herrmann


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.


Systemic lupus erythematosus (SLE) Resolution Inflammation Apoptosis Secondary necrosis Neutrophil extracellular traps (NETs) Clearance 


Funding information

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Bursch W, Ellinger A, Gerner C, Frohwein U, Schulte-Hermann R (2000) Programmed cell death (PCD). Apoptosis, autophagic PCD, or others? Ann N Y Acad Sci 926:1–12CrossRefGoogle Scholar
  2. 2.
    D'Arcy MS (2019) Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 43(6):582–592. CrossRefPubMedGoogle Scholar
  3. 3.
    Darzynkiewicz Z, Juan G, Li X, Gorczyca W, Murakami T, Traganos F (1997) Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis). Cytometry 27(1):1–20CrossRefGoogle Scholar
  4. 4.
    Cenciarelli C, Tanzarella C, Vitale I, Pisano C, Crateri P, Meschini S, Arancia G, Antoccia A (2008) The tubulin-depolymerising agent combretastatin-4 induces ectopic aster assembly and mitotic catastrophe in lung cancer cells H460. Apoptosis : an international journal on programmed cell death 13(5):659–669. CrossRefGoogle Scholar
  5. 5.
    Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663):1532–1535. CrossRefGoogle Scholar
  6. 6.
    Pieterse E, Rother N, Yanginlar C, Hilbrands LB, van der Vlag J (2016) Neutrophils discriminate between lipopolysaccharides of different bacterial sources and selectively release neutrophil extracellular traps. Front Immunol 7:484. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Rochael NC, Guimaraes-Costa AB, Nascimento MT, DeSouza-Vieira TS, Oliveira MP, Garcia e Souza LF, Oliveira MF, Saraiva EM (2015) Classical ROS-dependent and early/rapid ROS-independent release of neutrophil extracellular traps triggered by Leishmania parasites. Sci Rep 5:18302. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Mahajan A, Gruneboom A, Petru L, Podolska MJ, Kling L, Maueroder C, Dahms F, Christiansen S, Gunter L, Krenn V, Junemann A, Bock F, Schauer C, Schett G, Hohberger B, Herrmann M, Munoz LE (2019) Frontline Science: Aggregated neutrophil extracellular traps prevent inflammation on the neutrophil-rich ocular surface. J Leukoc Biol. CrossRefGoogle Scholar
  9. 9.
    Schauer C, Janko C, Munoz LE, Zhao Y, Kienhofer D, Frey B, Lell M, Manger B, Rech J, Naschberger E, Holmdahl R, Krenn V, Harrer T, Jeremic I, Bilyy R, Schett G, Hoffmann M, Herrmann M (2014) Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med 20(5):511–517. CrossRefPubMedGoogle Scholar
  10. 10.
    Appelt U, Sheriff A, Gaipl US, Kalden JR, Voll RE, Herrmann M (2005) Viable, apoptotic and necrotic monocytes expose phosphatidylserine: cooperative binding of the ligand Annexin V to dying but not viable cells and implications for PS-dependent clearance. Cell Death Differ 12(2):194–196. CrossRefPubMedGoogle Scholar
  11. 11.
    Meesmann HM, Fehr EM, Kierschke S, Herrmann M, Bilyy R, Heyder P, Blank N, Krienke S, Lorenz HM, Schiller M (2010) Decrease of sialic acid residues as an eat-me signal on the surface of apoptotic lymphocytes. J Cell Sci 123(Pt 19):3347–3356. CrossRefPubMedGoogle Scholar
  12. 12.
    Pieterse E, Hofstra J, Berden J, Herrmann M, Dieker J, van der Vlag J (2015) Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus. Clin Exp Immunol 179(1):68–74. CrossRefPubMedGoogle Scholar
  13. 13.
    Mahajan A, Herrmann M, Munoz LE (2016) Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE. Front Immunol 7:35. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Birge RB, Boeltz S, Kumar S, Carlson J, Wanderley J, Calianese D, Barcinski M, Brekken RA, Huang X, Hutchins JT, Freimark B, Empig C, Mercer J, Schroit AJ, Schett G, Herrmann M (2016) Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ 23(6):962–978. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Mikolajczyk TP, Skiba D, Batko B, Krezelok M, Wilk G, Osmenda G, Pryjma JR, Guzik TJ (2014) Characterization of the impairment of the uptake of apoptotic polymorphonuclear cells by monocyte subpopulations in systemic lupus erythematosus. Lupus 23(13):1358–1369. CrossRefPubMedGoogle Scholar
  16. 16.
    Fadok VA, Savill JS, Haslett C, Bratton DL, Doherty DE, Campbell PA, Henson PM (1992) Different populations of macrophages use either the vitronectin receptor or the phosphatidylserine receptor to recognize and remove apoptotic cells. J Immunol 149(12):4029–4035PubMedGoogle Scholar
  17. 17.
    Barth ND, Marwick JA, Vendrell M, Rossi AG, Dransfield I (2017) The “phagocytic synapse” and clearance of apoptotic cells. Front Immunol 8:1708. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Baumann I, Kolowos W, Voll RE, Manger B, Gaipl U, Neuhuber WL, Kirchner T, Kalden JR, Herrmann M (2002) Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum 46(1):191–201.<191::AID-ART10027>3.0.CO;2-K CrossRefPubMedGoogle Scholar
  19. 19.
    Trahtemberg U, Mevorach D (2017) Apoptotic cells induced signaling for immune homeostasis in macrophages and dendritic cells. Front Immunol 8:1356. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Sousa C, Pereira I, Santos AC, Carbone C, Kovacevic AB, Silva AM, Souto EB (2017) Targeting dendritic cells for the treatment of autoimmune disorders, colloids and surfaces. B, Biointerfaces 158:237–248. CrossRefPubMedGoogle Scholar
  21. 21.
    Hargraves MM (1949) Production in vitro of the L.E. cell phenomenon; use of normal bone marrow elements and blood plasma from patients with acute disseminated lupus erythematosus. Proc Staff Meet Mayo Clin 24(9):234–237PubMedGoogle Scholar
  22. 22.
    Schett G, Steiner G, Smolen JS (1998) Nuclear antigen histone H1 is primarily involved in lupus erythematosus cell formation. Arthritis Rheum 41(8):1446–1455.<1446::AID-ART15>3.0.CO;2-6 CrossRefPubMedGoogle Scholar
  23. 23.
    Bartl MM, Luckenbach T, Bergner O, Ullrich O, Koch-Brandt C (2001) Multiple receptors mediate apoJ-dependent clearance of cellular debris into nonprofessional phagocytes. Exp Cell Res 271(1):130–141. CrossRefPubMedGoogle Scholar
  24. 24.
    Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26(4):239–257CrossRefGoogle Scholar
  25. 25.
    Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR (1998) Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41(7):1241–1250.<1241::AID-ART15>3.0.CO;2-H CrossRefPubMedGoogle Scholar
  26. 26.
    Boeltz SK, Deborah, Markus H (2013) Wolves in sheep’s clothing: how chemically inert hydrocarbon oils induce autoimmunity. Immunome Res 9.
  27. 27.
    Henson PM, Bratton DL, Fadok VA (2001) Apoptotic cell removal. Current biology : CB 11(19):R795–R805CrossRefGoogle Scholar
  28. 28.
    Vandivier RW, Henson PM, Douglas IS (2006) Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 129(6):1673–1682. CrossRefPubMedGoogle Scholar
  29. 29.
    Biermann MH, Podolska MJ, Knopf J, Reinwald C, Weidner D, Maueroder C, Hahn J, Kienhofer D, Barras A, Boukherroub R, Szunerits S, Bilyy R, Hoffmann M, Zhao Y, Schett G, Herrmann M, Munoz LE (2016) Oxidative burst-dependent NETosis is implicated in the resolution of necrosis-associated sterile inflammation. Front Immunol 7:557. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Biermann MHC, Boeltz S, Pieterse E, Knopf J, Rech J, Bilyy R, van der Vlag J, Tincani A, Distler JHW, Kronke G, Schett GA, Herrmann M, Munoz LE (2018) Autoantibodies recognizing secondary NEcrotic cells promote neutrophilic phagocytosis and identify patients with systemic lupus erythematosus. Front Immunol 9:989. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Choi JJ, Reich CF 3rd, Pisetsky DS (2005) The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cells. Immunology 115(1):55–62. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Morimoto K, Janssen WJ, Fessler MB, McPhillips KA, Borges VM, Bowler RP, Xiao YQ, Kench JA, Henson PM, Vandivier RW (2006) Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease. J Immunol 176(12):7657–7665CrossRefGoogle Scholar
  33. 33.
    Thorp E, Subramanian M, Tabas I (2011) The role of macrophages and dendritic cells in the clearance of apoptotic cells in advanced atherosclerosis. Eur J Immunol 41(9):2515–2518. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Davidson A, Bethunaickan R, Berthier C, Sahu R, Zhang W, Kretzler M (2015) Molecular studies of lupus nephritis kidneys. Immunol Res 63(1–3):187–196. CrossRefPubMedGoogle Scholar
  35. 35.
    Hakkim A, Furnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A 107(21):9813–9818. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Elkon KB, Santer DM (2012) Complement, interferon and lupus. Curr Opin Immunol 24(6):665–670. CrossRefPubMedGoogle Scholar
  37. 37.
    Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL, Barrat FJ, Banchereau J, Pascual V (2011) Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 3(73):73ra20. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Zhang Y, Shi W, Tang S, Li J, Yin S, Gao X, Wang L, Zou L, Zhao J, Huang Y, Shan L, Gounni AS, Wu Y, Yuan F, Zhang J (2013) The influence of cathelicidin LL37 in human anti-neutrophils cytoplasmic antibody (ANCA)-associated vasculitis. Arthritis Res Ther 15(5):R161. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Munoz LE, Janko C, Chaurio RA, Schett G, Gaipl US, Herrmann M (2010) IgG opsonized nuclear remnants from dead cells cause systemic inflammation in SLE. Autoimmunity 43(3):232–235. CrossRefPubMedGoogle Scholar
  40. 40.
    Munoz LE, Janko C, Grossmayer GE, Frey B, Voll RE, Kern P, Kalden JR, Schett G, Fietkau R, Herrmann M, Gaipl US (2009) Remnants of secondarily necrotic cells fuel inflammation in systemic lupus erythematosus. Arthritis Rheum 60(6):1733–1742. CrossRefPubMedGoogle Scholar
  41. 41.
    Glass D, Raum D, Gibson D, Stillman JS, Schur PH (1976) Inherited deficiency of the second component of complement. Rheumatic disease associations. J Clin Invest 58(4):853–861. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Helve T, Kurki P, Teppo AM, Wegelius O (1983) DNA antibodies and complement in SLE patients. A follow-up study. Rheumatol Int 3(3):129–132CrossRefGoogle Scholar
  43. 43.
    Teppo AM, Kurki P, Helve T, Wegelius O (1984) DNA antibodies with and without complement-binding ability. Rheumatol Int 4(4):173–176CrossRefGoogle Scholar
  44. 44.
    Sekine H, Ruiz P, Gilkeson GS, Tomlinson S (2011) The dual role of complement in the progression of renal disease in NZB/W F(1) mice and alternative pathway inhibition. Mol Immunol 49(1–2):317–323. CrossRefPubMedGoogle Scholar
  45. 45.
    Breda L, Nozzi M, De Sanctis S, Chiarelli F (2010) Laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update. Semin Arthritis Rheum 40(1):53–72. CrossRefPubMedGoogle Scholar
  46. 46.
    Gaipl US, Beyer TD, Heyder P, Kuenkele S, Bottcher A, Voll RE, Kalden JR, Herrmann M (2004) Cooperation between C1q and DNase I in the clearance of necrotic cell-derived chromatin. Arthritis Rheum 50(2):640–649. CrossRefPubMedGoogle Scholar
  47. 47.
    Wang FM, Song D, Pang Y, Song Y, Yu F, Zhao MH (2016) The dysfunctions of complement factor H in lupus nephritis. Lupus 25(12):1328–1340. CrossRefPubMedGoogle Scholar
  48. 48.
    Machida T, Sakamoto N, Ishida Y, Takahashi M, Fujita T, Sekine H (2018) Essential roles for mannose-binding lectin-associated serine protease-1/3 in the development of lupus-like glomerulonephritis in MRL/lpr mice. Front Immunol 9:1191. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Martin M, Leffler J, Blom AM (2012) Annexin A2 and A5 serve as new ligands for C1q on apoptotic cells. J Biol Chem 287(40):33733–33744. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Ferry H, Potter PK, Crockford TL, Nijnik A, Ehrenstein MR, Walport MJ, Botto M, Cornall RJ (2007) Increased positive selection of B1 cells and reduced B cell tolerance to intracellular antigens in c1q-deficient mice. J Immunol 178(5):2916–2922CrossRefGoogle Scholar
  51. 51.
    Iram T, Ramirez-Ortiz Z, Byrne MH, Coleman UA, Kingery ND, Means TK, Frenkel D, El Khoury J (2016) Megf10 is a receptor for C1Q that mediates clearance of apoptotic cells by astrocytes. J Neurosci 36(19):5185–5192. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Quartier P, Potter PK, Ehrenstein MR, Walport MJ, Botto M (2005) Predominant role of IgM-dependent activation of the classical pathway in the clearance of dying cells by murine bone marrow-derived macrophages in vitro. Eur J Immunol 35(1):252–260. CrossRefPubMedGoogle Scholar
  53. 53.
    Mevorach D, Mascarenhas JO, Gershov D, Elkon KB (1998) Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med 188(12):2313–2320CrossRefGoogle Scholar
  54. 54.
    Blume KE, Soeroes S, Keppeler H, Stevanovic S, Kretschmer D, Rautenberg M, Wesselborg S, Lauber K (2012) Cleavage of annexin A1 by ADAM10 during secondary necrosis generates a monocytic “find-me” signal. J Immunol 188(1):135–145. CrossRefPubMedGoogle Scholar
  55. 55.
    Blume KE, Soeroes S, Waibel M, Keppeler H, Wesselborg S, Herrmann M, Schulze-Osthoff K, Lauber K (2009) Cell surface externalization of annexin A1 as a failsafe mechanism preventing inflammatory responses during secondary necrosis. J Immunol 183(12):8138–8147. CrossRefPubMedGoogle Scholar
  56. 56.
    Bruschi M, Petretto A, Vaglio A, Santucci L, Candiano G, Ghiggeri GM (2018) Annexin A1 and autoimmunity: from basic science to clinical applications. Int J Mol Sci 19(5). CrossRefGoogle Scholar
  57. 57.
    Kenis H, van Genderen H, Deckers NM, Lux PA, Hofstra L, Narula J, Reutelingsperger CP (2006) Annexin A5 inhibits engulfment through internalization of PS-expressing cell membrane patches. Exp Cell Res 312(6):719–726. CrossRefPubMedGoogle Scholar
  58. 58.
    Janko C, Jeremic I, Biermann M, Chaurio R, Schorn C, Munoz LE, Herrmann M (2013) Cooperative binding of Annexin A5 to phosphatidylserine on apoptotic cell membranes. Phys Biol 10(6):065006. CrossRefPubMedGoogle Scholar
  59. 59.
    Stach CM, Turnay X, Voll RE, Kern PM, Kolowos W, Beyer TD, Kalden JR, Herrmann M (2000) Treatment with annexin V increases immunogenicity of apoptotic human T-cells in Balb/c mice. Cell Death Differ 7(10):911–915. CrossRefPubMedGoogle Scholar
  60. 60.
    Bondanza A, Zimmermann VS, Rovere-Querini P, Turnay J, Dumitriu IE, Stach CM, Voll RE, Gaipl US, Bertling W, Poschl E, Kalden JR, Manfredi AA, Herrmann M (2004) Inhibition of phosphatidylserine recognition heightens the immunogenicity of irradiated lymphoma cells in vivo. J Exp Med 200(9):1157–1165. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gaipl US, Munoz LE, Rodel F, Pausch F, Frey B, Brachvogel B, von der Mark K, Poschl E (2007) Modulation of the immune system by dying cells and the phosphatidylserine-ligand annexin A5. Autoimmunity 40(4):254–259. CrossRefPubMedGoogle Scholar
  62. 62.
    Aleman OR, Mora N, Cortes-Vieyra R, Uribe-Querol E, Rosales C (2016) Differential use of human neutrophil Fcgamma receptors for inducing neutrophil extracellular trap formation. J Immunol Res 2016:2908034–2908017. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Behnen M, Leschczyk C, Moller S, Batel T, Klinger M, Solbach W, Laskay T (2014) Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcgammaRIIIB and Mac-1. J Immunol 193(4):1954–1965. CrossRefPubMedGoogle Scholar
  64. 64.
    Chen K, Nishi H, Travers R, Tsuboi N, Martinod K, Wagner DD, Stan R, Croce K, Mayadas TN (2012) Endocytosis of soluble immune complexes leads to their clearance by FcgammaRIIIB but induces neutrophil extracellular traps via FcgammaRIIA in vivo. Blood 120(22):4421–4431. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Lood C, Arve S, Ledbetter J, Elkon KB (2017) TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA. J Exp Med 214(7):2103–2119. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Perdomo J, Leung HHL, Ahmadi Z, Yan F, Chong JJH, Passam FH, Chong BH (2019) Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun 10(1):1322. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Andrade MF, Kabeya LM, Bortot LO, Santos GBD, Santos EOL, Albiero LR, Figueiredo-Rinhel ASG, Carvalho CA, Azzolini A, Caliri A, Pupo MT, Emery FS, Lucisano-Valim YM (2018) The 3-phenylcoumarin derivative 6,7-dihydroxy-3-[3′,4′-methylenedioxyphenyl]-coumarin downmodulates the FcgammaR- and CR-mediated oxidative metabolism and elastase release in human neutrophils: possible mechanisms underlying inhibition of the formation and release of neutrophil extracellular traps. Free Radic Biol Med 115:421–435. CrossRefPubMedGoogle Scholar
  68. 68.
    Horvei KD, Pedersen HL, Fismen S, Thiyagarajan D, Schneider A, Rekvig OP, Winkler TH, Seredkina N (2017) Lupus nephritis progression in FcgammaRIIB−/−yaa mice is associated with early development of glomerular electron dense deposits and loss of renal DNase I in severe disease. PLoS One 12(11):e0188863. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Weisenburger T, von Neubeck B, Schneider A, Ebert N, Schreyer D, Acs A, Winkler TH (2018) Epistatic interactions between mutations of deoxyribonuclease 1-like 3 and the inhibitory fc gamma receptor IIB result in very early and massive autoantibodies against double-stranded DNA. Front Immunol 9:1551. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Aleyd E, Al M, Tuk CW, van der Laken CJ, van Egmond M (2016) IgA complexes in plasma and synovial fluid of patients with rheumatoid arthritis induce neutrophil extracellular traps via FcalphaRI. J Immunol 197(12):4552–4559. CrossRefPubMedGoogle Scholar
  71. 71.
    Jimenez-Alcazar M, Rangaswamy C, Panda R, Bitterling J, Simsek YJ, Long AT, Bilyy R, Krenn V, Renne C, Renne T, Kluge S, Panzer U, Mizuta R, Mannherz HG, Kitamura D, Herrmann M, Napirei M, Fuchs TA (2017) Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science 358(6367):1202–1206. CrossRefPubMedGoogle Scholar
  72. 72.
    Fenton KA, Rekvig OP (2007) A central role of nucleosomes in lupus nephritis. Ann N Y Acad Sci 1108:104–113CrossRefGoogle Scholar
  73. 73.
    Zykova SN, Seredkina N, Benjaminsen J, Rekvig OP (2008) Reduced fragmentation of apoptotic chromatin is associated with nephritis in lupus-prone (NZB x NZW)F(1) mice. Arthritis Rheum 58(3):813–825. CrossRefPubMedGoogle Scholar
  74. 74.
    Mjelle JE, Kalaaji M, Rekvig OP (2009) Exposure of chromatin and not high affinity for dsDNA determines the nephritogenic impact of anti-dsDNA antibodies in (NZBxNZW)F1 mice. Autoimmunity 42(2):104–111. CrossRefPubMedGoogle Scholar
  75. 75.
    Fismen S, Mortensen ES, Rekvig OP (2011) Nuclease deficiencies promote end-stage lupus nephritis but not nephritogenic autoimmunity in (NZB x NZW) F1 mice. Immunol Cell Biol 89(1):90–99. CrossRefPubMedGoogle Scholar
  76. 76.
    Fenton K, Fismen S, Hedberg A, Seredkina N, Fenton C, Mortensen ES, Rekvig OP (2009) Anti-dsDNA antibodies promote initiation, and acquired loss of renal Dnase1 promotes progression of lupus nephritis in autoimmune (NZBxNZW)F1 mice. PLoS One 4(12):e8474. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Hedberg A, Fismen S, Fenton KA, Mortensen ES, Rekvig OP (2010) Deposition of chromatin-IgG complexes in skin of nephritic MRL-lpr/lpr mice is associated with increased local matrix metalloprotease activities. Exp Dermatol 19(8):e265–e274. CrossRefPubMedGoogle Scholar
  78. 78.
    Thiyagarajan D, Rekvig OP, Seredkina N (2015) TNFalpha amplifies DNaseI expression in renal tubular cells while IL-1beta promotes nuclear DNaseI translocation in an endonuclease-inactive form. PLoS One 10(6):e0129485. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Gershwin ME, Shultz L (1985) Mechanisms of genetically determined immune dysfunction. Immunol Today 6(2):36–37. CrossRefPubMedGoogle Scholar
  80. 80.
    Pedersen HL, Horvei KD, Thiyagarajan D, Norby GE, Seredkina N, Moroni G, Eilertsen GO, Holdaas H, Strom EH, Bakland G, Meroni PL, Rekvig OP (2018) Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression. The journal of pathology Clinical research 4(3):193–203. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Yagnik DR, Hillyer P, Marshall D, Smythe CD, Krausz T, Haskard DO, Landis RC (2000) Noninflammatory phagocytosis of monosodium urate monohydrate crystals by mouse macrophages. Implications for the control of joint inflammation in gout. Arthritis Rheum 43(8):1779–1789.<1779::AID-ANR14>3.0.CO;2-2 CrossRefPubMedGoogle Scholar
  82. 82.
    Yuan XM, Li W, Brunk UT, Dalen H, Chang YH, Sevanian A (2000) Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products. Free Radic Biol Med 28(2):208–218CrossRefGoogle Scholar
  83. 83.
    Cui D, Thorp E, Li Y, Wang N, Yvan-Charvet L, Tall AR, Tabas I (2007) Pivotal advance: macrophages become resistant to cholesterol-induced death after phagocytosis of apoptotic cells. J Leukoc Biol 82(5):1040–1050. CrossRefPubMedGoogle Scholar
  84. 84.
    Li Y, Gerbod-Giannone MC, Seitz H, Cui D, Thorp E, Tall AR, Matsushima GK, Tabas I (2006) Cholesterol-induced apoptotic macrophages elicit an inflammatory response in phagocytes, which is partially attenuated by the Mer receptor. J Biol Chem 281(10):6707–6717. CrossRefPubMedGoogle Scholar
  85. 85.
    Hamon Y, Broccardo C, Chambenoit O, Luciani MF, Toti F, Chaslin S, Freyssinet JM, Devaux PF, McNeish J, Marguet D, Chimini G (2000) ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine. Nat Cell Biol 2(7):399–406. CrossRefPubMedGoogle Scholar
  86. 86.
    Grainger DJ, Reckless J, McKilligin E (2004) Apolipoprotein E modulates clearance of apoptotic bodies in vitro and in vivo, resulting in a systemic proinflammatory state in apolipoprotein E-deficient mice. J Immunol 173(10):6366–6375CrossRefGoogle Scholar
  87. 87.
    Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y, Yoshioka Y, Yoshikawa H, Nagata S (2006) Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443(7114):998–1002. CrossRefPubMedGoogle Scholar
  88. 88.
    Ippolito A, Petri M (2008) An update on mortality in systemic lupus erythematosus. Clin Exp Rheumatol 26(5 Suppl 51):S72–S79PubMedGoogle Scholar
  89. 89.
    Maria NI, Davidson A (2017) Renal macrophages and dendritic cells in SLE nephritis. Curr Rheumatol Rep 19(12):81. CrossRefPubMedGoogle Scholar
  90. 90.
    Ravishankar B, Liu H, Shinde R, Chaudhary K, Xiao W, Bradley J, Koritzinsky M, Madaio MP, McGaha TL (2015) The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity. Proc Natl Acad Sci U S A 112(34):10774–10779. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Marek I, Becker R, Fahlbusch FB, Menendez-Castro C, Rascher W, Daniel C, Volkert G, Hartner A (2018) Expression of the Alpha8 integrin chain facilitates phagocytosis by renal mesangial cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 45(6):2161–2173. CrossRefGoogle Scholar
  92. 92.
    Kimura T, Isaka Y, Yoshimori T (2017) Autophagy and kidney inflammation. Autophagy 13(6):997–1003. CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Brooks CR, Yeung MY, Brooks YS, Chen H, Ichimura T, Henderson JM, Bonventre JV (2015) KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation. EMBO J 34(19):2441–2464. CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Yang L, Brooks CR, Xiao S, Sabbisetti V, Yeung MY, Hsiao LL, Ichimura T, Kuchroo V, Bonventre JV (2015) KIM-1-mediated phagocytosis reduces acute injury to the kidney. J Clin Invest 125(4):1620–1636. CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Ismail OZ, Sriranganathan S, Zhang X, Bonventre JV, Zervos AS, Gunaratnam L (2018) Tctex-1, a novel interaction partner of kidney injury molecule-1, is required for efferocytosis. J Cell Physiol 233(10):6877–6895. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Cen C, Aziz M, Yang WL, Zhou M, Nicastro JM, Coppa GF, Wang P (2017) Milk fat globule-epidermal growth factor-factor VIII attenuates sepsis-induced acute kidney injury. J Surg Res 213:281–289. CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, Scadden DT, Wagner DD (2012) Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U S A 109(32):13076–13081. CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 107(36):15880–15885. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Chitrabamrung S, Rubin RL, Tan EM (1981) Serum deoxyribonuclease I and clinical activity in systemic lupus erythematosus. Rheumatol Int 1(2):55–60CrossRefGoogle Scholar
  100. 100.
    Al-Mayouf SM, Sunker A, Abdwani R, Abrawi SA, Almurshedi F, Alhashmi N, Al Sonbul A, Sewairi W, Qari A, Abdallah E, Al-Owain M, Al Motywee S, Al-Rayes H, Hashem M, Khalak H, Al-Jebali L, Alkuraya FS (2011) Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet 43(12):1186–1188. CrossRefPubMedGoogle Scholar
  101. 101.
    Leppkes M, Maueroder C, Hirth S, Nowecki S, Gunther C, Billmeier U, Paulus S, Biermann M, Munoz LE, Hoffmann M, Wildner D, Croxford AL, Waisman A, Mowen K, Jenne DE, Krenn V, Mayerle J, Lerch MM, Schett G, Wirtz S, Neurath MF, Herrmann M, Becker C (2016) Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis. Nat Commun 7:10973. CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Maueroder C, Mahajan A, Paulus S, Gosswein S, Hahn J, Kienhofer D, Biermann MH, Tripal P, Friedrich RP, Munoz LE, Neurath MF, Becker C, Schett GA, Herrmann M, Leppkes M (2016) Menage-a-trois: the ratio of bicarbonate to CO2 and the pH regulate the capacity of neutrophils to form NETs. Front Immunol 7:583. CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Bilyy R, Fedorov V, Vovk V, Leppkes M, Dumych T, Chopyak V, Schett G, Herrmann M (2016) Neutrophil extracellular traps form a barrier between necrotic and viable areas in acute abdominal inflammation. Front Immunol 7:424. CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Kalra MG, Higgins KE, Kinney BS (2014) Intertrigo and secondary skin infections. Am Fam Physician 89(7):569–573PubMedGoogle Scholar
  105. 105.
    Greidinger EL, Casciola-Rosen L, Morris SM, Hoffman RW, Rosen A (2000) Autoantibody recognition of distinctly modified forms of the U1-70-kd antigen is associated with different clinical disease manifestations. Arthritis Rheum 43(4):881–888.<881::AID-ANR20>3.0.CO;2-G CrossRefPubMedGoogle Scholar
  106. 106.
    Hall JC, Casciola-Rosen L, Rosen A (2004) Altered structure of autoantigens during apoptosis. Rheum Dis Clin N Am 30(3):455–471, vii. CrossRefGoogle Scholar
  107. 107.
    Crow MK (2014) Advances in understanding the role of type I interferons in systemic lupus erythematosus. Curr Opin Rheumatol 26(5):467–474. CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Krapf F, Herrmann M, Leitmann W, Kalden JR (1989) Antibody binding of macromolecular DNA and RNA in the plasma of SLE patients. Clin Exp Immunol 75(3):336–342PubMedPubMedCentralGoogle Scholar
  109. 109.
    Gheorghiu M (1996) The ocular manifestations in systemic lupus erythematosus. Oftalmologia 40(2):100–104PubMedGoogle Scholar
  110. 110.
    Preble JM, Silpa-archa S, Foster CS (2015) Ocular involvement in systemic lupus erythematosus. Curr Opin Ophthalmol 26(6):540–545. CrossRefPubMedGoogle Scholar
  111. 111.
    Thanabalasuriar A, Scott BNV, Peiseler M, Willson ME, Zeng Z, Warrener P, Keller AE, Surewaard BGJ, Dozier EA, Korhonen JT, Cheng LI, Gadjeva M, Stover CK, DiGiandomenico A, Kubes P (2019) Neutrophil extracellular traps confine Pseudomonas aeruginosa ocular biofilms and restrict brain invasion. Cell host & microbe 25(4):526–536 e4. CrossRefGoogle Scholar
  112. 112.
    Mohanty T, Sjogren J, Kahn F, Abu-Humaidan AH, Fisker N, Assing K, Morgelin M, Bengtsson AA, Borregaard N, Sorensen OE (2015) A novel mechanism for NETosis provides antimicrobial defense at the oral mucosa. Blood 126(18):2128–2137. CrossRefPubMedGoogle Scholar
  113. 113.
    Papillon MM, Lefèvre P (1924) Deux cas de kératodermie palmaire et plantaire symétrique familiale (maladie de Meleda) chez le frère et la soeur., Bulletin de la Société française de dermatologie et de vénéorologie, Paris. Deux cas de kératodermie palmaire et plantaire symétrique familiale (maladie de Meleda) chez le frère et la soeur. Coexistence dans les deux cas d’altérations dentaires graves 31:82–87Google Scholar
  114. 114.
    Dekker G, Jansen LH (1956) Hyperkeratosis palmo-plantaris with periodontosis (Papillon-Lefevre). Dermatologica 113(4):207–219CrossRefGoogle Scholar
  115. 115.
    Hahn J, Schauer C, Czegley C, Kling L, Petru L, Schmid B, Weidner D, Reinwald C, Biermann MHC, Blunder S, Ernst J, Lesner A, Bauerle T, Palmisano R, Christiansen S, Herrmann M, Bozec A, Gruber R, Schett G, Hoffmann MH (2019) Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33(1):1401–1414. CrossRefGoogle Scholar
  116. 116.
    Hartl D (2015) Oral NETs: the deadly kiss. Blood 126(18):2079–2080. CrossRefPubMedGoogle Scholar
  117. 117.
    Schiodt M (1984) Oral discoid lupus erythematosus. II. Skin lesions and systemic lupus erythematosus in sixty-six patients with 6-year follow-up. Oral surgery, oral medicine, and oral pathology 57(2):177–180CrossRefGoogle Scholar
  118. 118.
    Zuercher AW, Spirig R, Baz Morelli A, Rowe T, Kasermann F (2019) Next-generation Fc receptor-targeting biologics for autoimmune diseases. Autoimmun Rev 102366:102366. CrossRefGoogle Scholar
  119. 119.
    Lood C, Allhorn M, Lood R, Gullstrand B, Olin AI, Ronnblom L, Truedsson L, Collin M, Bengtsson AA (2012) IgG glycan hydrolysis by endoglycosidase S diminishes the proinflammatory properties of immune complexes from patients with systemic lupus erythematosus: a possible new treatment? Arthritis Rheum 64(8):2698–2706. CrossRefPubMedGoogle Scholar
  120. 120.
    Gomez-Guzman M, Jimenez R, Romero M, Sanchez M, Zarzuelo MJ, Gomez-Morales M, O'Valle F, Lopez-Farre AJ, Algieri F, Galvez J, Perez-Vizcaino F, Sabio JM, Duarte J (2014) Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus. Hypertension 64(2):330–337. CrossRefPubMedGoogle Scholar
  121. 121.
    Virdis A, Tani C, Duranti E, Vagnani S, Carli L, Kuhl AA, Solini A, Baldini C, Talarico R, Bombardieri S, Taddei S, Mosca M (2015) Early treatment with hydroxychloroquine prevents the development of endothelial dysfunction in a murine model of systemic lupus erythematosus. Arthritis research & therapy 17:277. CrossRefGoogle Scholar
  122. 122.
    Kienhofer D, Boeltz S, Hoffmann MH (2016) Reactive oxygen homeostasis - the balance for preventing autoimmunity. Lupus 25(8):943–954. CrossRefPubMedGoogle Scholar
  123. 123.
    Lauber K, Keppeler H, Munoz LE, Koppe U, Schroder K, Yamaguchi H, Kronke G, Uderhardt S, Wesselborg S, Belka C, Nagata S, Herrmann M (2013) Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids. Cell Death Differ 20(9):1230–1240. CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M (1995) Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 270(5234):286–290CrossRefGoogle Scholar
  125. 125.
    Cronstein BN, Eberle MA, Gruber HE, Levin RI (1991) Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci U S A 88(6):2441–2445. CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM (1999) BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285(5425):260–263CrossRefGoogle Scholar
  127. 127.
    Yildirim-Toruner C, Diamond B (2011) Current and novel therapeutics in the treatment of systemic lupus erythematosus. J Allergy Clin Immunol 127(2):303–312; quiz 313-4. CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Gottschalk TA, Tsantikos E, Hibbs ML (2015) Pathogenic inflammation and its therapeutic targeting in systemic lupus erythematosus. Front Immunol 6:550. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sebastian Boeltz
    • 1
  • Melanie Hagen
    • 1
  • Jasmin Knopf
    • 1
  • Aparna Mahajan
    • 1
  • Maximilian Schick
    • 1
  • Yi Zhao
    • 2
    • 1
  • Cornelia Erfurt-Berge
    • 3
  • Jürgen Rech
    • 1
  • Luis E. Muñoz
    • 1
    • 4
    Email author
  • Martin Herrmann
    • 1
  1. 1.Department of Internal Medicine 3 – Rheumatology and ImmunologyFriedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum ErlangenErlangenGermany
  2. 2.Department of Rheumatology and Immunology, West China HospitalSichuan UniversityChengduChina
  3. 3.Department of DermatologyFriedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum ErlangenErlangenGermany
  4. 4.Department of Internal Medicine 3Universitätsklinikum ErlangenErlangenGermany

Personalised recommendations