Burning controversies in NETs and autoimmunity: The mysteries of cell death and autoimmune disease

References

• Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–1535.
   PubMed Web of Science ®Google Scholar
• Lee KH, Kronbichler A, Park DD, et al. Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review. Autoimmun Rev. 2017;16:1160–1173.
   PubMed Web of Science ®Google Scholar
• Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23:279–287.
   PubMed Web of Science ®Google Scholar
• Dwivedi N, Radic M. Citrullination of autoantigens implicates NETosis in the induction of autoimmunity. Ann Rheum Dis. 2014;73:483–491.
   PubMed Web of Science ®Google Scholar
• Green DR, Ferguson T, Zitvogel L, et al. Immunogenic and tolerogenic cell death. Nat Rev Immunol. 2009;9:353–363.
   PubMed Web of Science ®Google Scholar
• Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1–5.
   PubMed Web of Science ®Google Scholar
• Mistry P, Kaplan MJ. Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis. Clin Immunol. 2017;185:59–73.
   PubMed Web of Science ®Google Scholar
• Nagata S, Hanayama R, Kawane K. Autoimmunity and the clearance of dead cells. Cell 2010;140:619–630.
   PubMed Web of Science ®Google Scholar
• Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–257.
   PubMed Web of Science ®Google Scholar
• Krammer PH. CD95's deadly mission in the immune system. Nature. 2000;407:789–795.
   PubMed Web of Science ®Google Scholar
• Nagata S. Apoptosis by death factor. Cell. 1997;88:355–365.
   PubMed Web of Science ®Google Scholar
• Ow YP, Green DR, Hao Z, et al. Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol. 2008;9:532–542.
   PubMed Web of Science ®Google Scholar
• Strasser A, Jost PJ, Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity. 2009;30:180–192.
   PubMed Web of Science ®Google Scholar
• Enari M, Sakahira H, Yokoyama H, et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 1998;391:43–50.
   PubMed Web of Science ®Google Scholar
• Sakahira H, Iwamatsu A, Nagata S. Specific chaperone-like activity of inhibitor of caspase-activated DNase for caspase-activated DNase. J Biol Chem. 2000;275:8091–8096.
   PubMed Web of Science ®Google Scholar
• Coleman ML, Sahai EA, Yeo M, et al. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol. 2001;3:339–345.
   PubMed Web of Science ®Google Scholar
• Cocca BA, Cline AM, Radic MZ. Blebs and apoptotic bodies are B cell autoantigens. J Immunol. 2002;169:159–166.
   PubMed Web of Science ®Google Scholar
• Radic M, Marion T, Monestier M. Nucleosomes are exposed at the cell surface in apoptosis. J Immunol. 2004;172:6692–6700.
   PubMed Web of Science ®Google Scholar
• Ogden CA, deCathelineau A, Hoffmann PR, et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med. 2001;194:781–795.
   PubMed Web of Science ®Google Scholar
• Familian A, Zwart B, Huisman HG, et al. Chromatin-independent binding of serum amyloid P component to apoptotic cells. J Immunol. 2001;167:647–654.
   PubMed Web of Science ®Google Scholar
• Du Clos TW, Zlock LT, Marnell L. Definition of a C-reactive protein binding determinant on histones. J Biol Chem. 1991;266:2167–2171.
   PubMed Web of Science ®Google Scholar
• Asano K, Miwa M, Miwa K, et al. Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J Exp Med. 2004;200:459–467.
   PubMed Web of Science ®Google Scholar
• Baruah P, Propato A, Dumitriu IE, et al. The pattern recognition receptor PTX3 is recruited at the synapse between dying and dendritic cells, and edits the cross-presentation of self, viral, and tumor antigens. Blood. 2006;107:151–158.
   PubMed Web of Science ®Google Scholar
• Lemke G. Phosphatidylserine is the signal for TAM receptors and their ligands. Trends Biochem Sci. 2017;42:738–748.
   PubMed Web of Science ®Google Scholar
• Hanayama R, Tanaka M, Miyasaka K, et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science. 2004;304:1147–1150.
   PubMed Web of Science ®Google Scholar
• Kawane K, Ohtani M, Miwa K, et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature. 2006;443:998–1002.
   PubMed Web of Science ®Google Scholar
• Lu Q, Lemke G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science. 2001;293:306–311.
   PubMed Web of Science ®Google Scholar
• Radic MZ, Shah K, Zhang W, et al. Heterogeneous nuclear ribonucleoprotein P2 is an autoantibody target in mice deficient for Mer, Axl, and Tyro3 receptor tyrosine kinases. J Immunol. 2006;176:68–74.
   PubMed Web of Science ®Google Scholar
• Vandenabeele P, Galluzzi L, Vanden Berghe T, et al. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010;11:700–714.
   PubMed Web of Science ®Google Scholar
• Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137:1112–1123.
   PubMed Web of Science ®Google Scholar
• Hitomi J, Christofferson DE, Ng A, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell. 2008;135:1311–1323.
   PubMed Web of Science ®Google Scholar
• Moquin DM, McQuade T, Chan FK. CYLD deubiquitinates RIP1 in the TNFalpha-induced necrosome to facilitate kinase activation and programmed necrosis. PLoS One. 2013;8:e76841.
   PubMed Web of Science ®Google Scholar
• Schreiber A, Rousselle A, Becker JU, et al. Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis. Proc Natl Acad Sci USA. 2017;114:E9618–E9625.
   PubMed Web of Science ®Google Scholar
• Amini P, Stojkov D, Wang X, et al. NET formation can occur independently of RIPK3 and MLKL signaling. Eur J Immunol. 2016;46:178–184.
   PubMed Web of Science ®Google Scholar
• Gaipl US, Kuenkele S, Voll RE, et al. Complement binding is an early feature of necrotic and a rather late event during apoptotic cell death. Cell Death Differ. 2001;8:327–334.
   PubMed Web of Science ®Google Scholar
• Krysko DV, Denecker G, Festjens N, et al. Macrophages use different internalization mechanisms to clear apoptotic and necrotic cells. Cell Death Differ. 2006;13:2011–2022.
   PubMed Web of Science ®Google Scholar
• Bickerstaff MC, Botto M, Hutchinson WL, et al. Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med. 1999;5:694–697.
   PubMed Web of Science ®Google Scholar
• Wu X, Molinaro C, Johnson N, Casiano CA. Secondary necrosis is a source of proteolytically modified forms of specific intracellular autoantigens: implications for systemic autoimmunity. Arthritis Rheum. 2001;44:2642–2652.
   PubMed Web of Science ®Google Scholar
• Sachet M, Liang YY, Oehler R. The immune response to secondary necrotic cells. Apoptosis. 2017;22:1189–1204.
   PubMed Web of Science ®Google Scholar
• Spengler J, Lugonja B, Ytterberg AJ, et al. Release of active peptidyl arginine deiminases by neutrophils can explain production of extracellular citrullinated autoantigens in rheumatoid arthritis synovial fluid. Arthritis Rheumatol. 2015;67:3135–3145.
   PubMed Web of Science ®Google Scholar
• Hu SC, Yu HS, Yen FL, et al. Neutrophil extracellular trap formation is increased in psoriasis and induces human beta-defensin-2 production in epidermal keratinocytes. Sci Rep. 2016;6:31119.
   PubMed Web of Science ®Google Scholar
• Yipp BG, Kubes P. NETosis: how vital is it? Blood. 2013;122:2784–2794.
   PubMed Web of Science ®Google Scholar
• Mori Y, Yamaguchi M, Terao Y, et al. alpha-Enolase of Streptococcus pneumoniae induces formation of neutrophil extracellular traps. J Biol Chem. 2012;287:10472–10481.
   PubMed Web of Science ®Google Scholar
• Marin-Esteban V, Turbica I, Dufour G, et al. Afa/Dr diffusely adhering Escherichia coli strain C1845 induces neutrophil extracellular traps that kill bacteria and damage human enterocyte-like cells. Infect Immun. 2012;80:1891–1899.
   PubMed Web of Science ®Google Scholar
• Byrd AS, O'Brien XM, Johnson CM, et al. An extracellular matrix-based mechanism of rapid neutrophil extracellular trap formation in response to Candida albicans. J Immunol. 2013;190:4136–4148.
   PubMed Web of Science ®Google Scholar
• Bianchi M, Hakkim A, Brinkmann V, et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009;114:2619–2622.
   PubMed Web of Science ®Google Scholar
• Bruns S, Kniemeyer O, Hasenberg M, et al. Production of extracellular traps against Aspergillus fumigatus in vitro and in infected lung tissue is dependent on invading neutrophils and influenced by hydrophobin RodA. PLoS Pathog. 2010;6:e1000873.
   PubMed Web of Science ®Google Scholar
• Baker VS, Imade GE, Molta NB, et al. 3rd, Cytokine-associated neutrophil extracellular traps and antinuclear antibodies in Plasmodium falciparum infected children under six years of age. Malar J. 2008;7:41.
   PubMed Web of Science ®Google Scholar
• Waisberg M, Molina-Cruz A, Mizurini DM, et al. Plasmodium falciparum infection induces expression of a mosquito salivary protein (Agaphelin) that targets neutrophil function and inhibits thrombosis without impairing hemostasis. PLoS Pathog. 2014;10:e1004338.
   PubMed Web of Science ®Google Scholar
• Abi Abdallah DS, Lin C, Ball CJ, et al. Toxoplasma gondii triggers release of human and mouse neutrophil extracellular traps. Infect Immun. 2012;80:768–777.
   PubMed Web of Science ®Google Scholar
• Saitoh T, Komano J, Saitoh Y, et al. Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1. Cell Host Microbe. 2012;12:109–116.
   PubMed Web of Science ®Google Scholar
• Funchal GA, Jaeger N, Czepielewski RS, et al. Respiratory syncytial virus fusion protein promotes TLR-4-dependent neutrophil extracellular trap formation by human neutrophils. PLoS One. 2015;10:e0124082.
   PubMed Web of Science ®Google Scholar
• Maueroder C, Kienhofer D, Hahn J, et al. How neutrophil extracellular traps orchestrate the local immune response in gout. J Mol Med. 2015;93:727–734.
   PubMed Web of Science ®Google Scholar
• Behnen M, Leschczyk C, Moller S, et al. Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcgammaRIIIB and Mac-1. JI. 2014;193:1954–1965.
   Google Scholar
• Chen K, Nishi H, Travers R, et al. Endocytosis of soluble immune complexes leads to their clearance by FcgammaRIIIB but induces neutrophil extracellular traps via FcgammaRIIA in vivo. Blood. 2012;120:4421–4431.
   PubMedGoogle Scholar
• Neeli I, Dwivedi N, Khan S, Radic M. Regulation of extracellular chromatin release from neutrophils. J Innate Immun. 2009;1:194–201.
   PubMed Web of Science ®Google Scholar
• Yipp BG, Petri B, Salina D, et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med. 2012;18:1386–1393.
   PubMed Web of Science ®Google Scholar
• Fuchs TA, Abed U, Goosmann C, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176:231–241.
   PubMed Web of Science ®Google Scholar
• Wang Y, Li M, Stadler S, et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol. 2009;184:205–213.
   PubMed Web of Science ®Google Scholar
• Li P, Li M, Lindberg MR, et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med. 2010;207:1853–1862.
   PubMed Web of Science ®Google Scholar
• Hakkim A, Fuchs TA, Martinez NE, et al. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat Chem Biol. 2011;7:75–77.
   PubMed Web of Science ®Google Scholar
• Neeli I, Radic M. Opposition between PKC isoforms regulates histone deimination and neutrophil extracellular chromatin release. Front Immun. 2013;4:38.
   PubMed Web of Science ®Google Scholar
• Douda DN, Khan MA, Grasemann H, Palaniyar N. SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx. Proc Natl Acad Sci USA. 2015;112:2817–2822.
   PubMed Web of Science ®Google Scholar
• Munoz-Caro T, Lendner M, Daugschies A, et al. NADPH oxidase, MPO, NE, ERK1/2, p38 MAPK and Ca2+ influx are essential for Cryptosporidium parvum-induced NET formation. Development Compara Immunol. 2015;52:245–254.
   PubMed Web of Science ®Google Scholar
• Makni-Maalej K, Chiandotto M, Hurtado-Nedelec M, et al. Zymosan induces NADPH oxidase activation in human neutrophils by inducing the phosphorylation of p47phox and the activation of Rac2: involvement of protein tyrosine kinases, PI3Kinase, PKC, ERK1/2 and p38MAPkinase. Biochem Pharmacol. 2013;85:92–100.
   PubMed Web of Science ®Google Scholar
• Dwivedi N, Neeli I, Schall N, et al. Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity. FASEB J. 2014;28:2840–2851.
   PubMed Web of Science ®Google Scholar
• Neeli I, Khan SN, Radic M. Histone deimination as a response to inflammatory stimuli in neutrophils. J Immunol. 2008;180:1895–1902.
   PubMed Web of Science ®Google Scholar
• Thanarajasingam U, Jensen MA, Dorschner JM, et al. Brief report: a novel ELANE mutation associated with inflammatory arthritis, defective netosis, and recurrent parvovirus infection. Arthritis Rheumatol. 2017;69:2396–2401.
   PubMed Web of Science ®Google Scholar
• Wartha F, Beiter K, Albiger B, et al. Capsule and D-alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps. Cell Microbiol. 2007;9:1162–1171.
   PubMed Web of Science ®Google Scholar
• Beiter K, Wartha F, Albiger B, et al. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Current Biology: CB. 2006;16:401–407.
   PubMed Web of Science ®Google Scholar
• Buchanan JT, Simpson AJ, Aziz RK, et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol. 2006;16:396–400.
   PubMed Web of Science ®Google Scholar
• Seper A, Hosseinzadeh A, Gorkiewicz G, et al. Vibrio cholerae evades neutrophil extracellular traps by the activity of two extracellular nucleases. PLoS Pathog. 2013;9:e1003614.
   PubMed Web of Science ®Google Scholar
• Vong L, Lorentz RJ, Assa A, et al. Probiotic Lactobacillus rhamnosus inhibits the formation of neutrophil extracellular traps. J Immunol. 2014;192:1870–1877.
   PubMed Web of Science ®Google Scholar
• Urban CF, Ermert D, Schmid M, et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009;5:e1000639.
   PubMed Web of Science ®Google Scholar
• Kessenbrock K, Krumbholz M, Schonermarck U, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009;15:623–625.
   PubMed Web of Science ®Google Scholar
• Halverson TW, Wilton M, Poon KK, et al. DNA is an antimicrobial component of neutrophil extracellular traps. PLoS Pathog. 2015;11:e1004593.
   PubMed Web of Science ®Google Scholar
• Parseghian MH, Luhrs KA. Beyond the walls of the nucleus: the role of histones in cellular signaling and innate immunity. Biochem Cell Biol. 2006;84:589–604.
   PubMed Web of Science ®Google Scholar
• Wardemann H, Yurasov S, Schaefer A, et al. Predominant autoantibody production by early human B cell precursors. Science 2003;301:1374–1377.
   PubMed Web of Science ®Google Scholar
• Warshakoon HJ, Hood JD, Kimbrell MR, et al. Potential adjuvantic properties of innate immune stimuli. Human Vaccines. 2009;5:381–394.
   PubMed Web of Science ®Google Scholar
• Weinstein JS, Hernandez SG, Craft J. T cells that promote B-cell maturation in systemic autoimmunity. Immunol Rev. 2012;247:160–171.
   PubMed Web of Science ®Google Scholar
• Yang D, de la Rosa G, Tewary P, et al. Alarmins link neutrophils and dendritic cells. Trends Immunol. 2009;30:531–537.
   PubMed Web of Science ®Google Scholar
• Grund LZ, Novaski I, Quesniaux VF, et al. Neutrophils releasing IL-17A into NETs are essential to plasma cell differentiation in inflamed tissue dependent on IL-1R. Autoimmunity. 2017;50:86–101.
   PubMed Web of Science ®Google Scholar
• Xu J, Zhang X, Monestier M, et al. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol. 2011;187:2626–2631.
   PubMed Web of Science ®Google Scholar
• Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15:1318–1321.
   PubMed Web of Science ®Google Scholar
• Villanueva E, Yalavarthi S, Berthier CC, et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol. 2011;187:538–552.
   PubMed Web of Science ®Google Scholar
• Fuchs TA, Brill A, Duerschmied D, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA. 2010;107:15880–15885.
   PubMed Web of Science ®Google Scholar
• Jimenez-Alcazar M, Rangaswamy C, Panda R, et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science. 2017;358:1202–1206.
   PubMed Web of Science ®Google Scholar
• Skopelja S, Hamilton BJ, Jones JD, et al. The role for neutrophil extracellular traps in cystic fibrosis autoimmunity. JCI Insight. 2016;1:e88912.
   PubMed Web of Science ®Google Scholar
• Hill JA, Southwood S, Sette A, et al. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol. 2003;171:538–541.
   PubMed Web of Science ®Google Scholar
• Quinn MA, Gough AK, Green MJ, et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology. 2006;45:478–480.
   PubMed Web of Science ®Google Scholar
• Ronnelid J, Wick MC, Lampa J, et al. Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression. Ann Rheumatic Dis. 2005;64:1744–1749.
   PubMed Web of Science ®Google Scholar
• Kuhn KA, Kulik L, Tomooka B, et al. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest. 2006;116:961–973.
   PubMed Web of Science ®Google Scholar
• Clavel C, Nogueira L, Laurent L, et al. Induction of macrophage secretion of tumor necrosis factor alpha through Fcgamma receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum. 2008;58:678–688.
   PubMed Web of Science ®Google Scholar
• Trouw LA, Haisma EM, Levarht EW, et al. Anti-cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways. Arthritis Rheum. 2009;60:1923–1931.
   PubMed Web of Science ®Google Scholar
• Baumann I, Kolowos W, Voll RE, et al. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum. 2002;46:191–201.
   PubMed Web of Science ®Google Scholar
• Das A, Heesters BA, Bialas A, et al. Follicular dendritic cell activation by TLR ligands promotes autoreactive B cell responses. Immunity. 2017;46:106–119.
   PubMed Web of Science ®Google Scholar
• Hakkim A, Furnrohr BG, Amann K, et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA. 2010;107:9813–9818.
   PubMed Web of Science ®Google Scholar
• Yeh TM, Chang HC, Liang CC, et al. Deoxyribonuclease-inhibitory antibodies in systemic lupus erythematosus. J Biomed Sci. 2003;10:544–551.
   PubMed Web of Science ®Google Scholar
• Leffler J, Martin M, Gullstrand B, et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol. 2012;188:3522–3531.
   PubMed Web of Science ®Google Scholar
• Humphreys JH, van Nies JA, Chipping J, et al. Rheumatoid factor and anti-citrullinated protein antibody positivity, but not level, are associated with increased mortality in patients with rheumatoid arthritis: results from two large independent cohorts. Arthritis Res Ther. 2014;16:483.
   PubMed Web of Science ®Google Scholar
• Sun B, Dwivedi N, Bechtel TJ, et al. Citrullination of NF-kappaB p65 promotes its nuclear localization and TLR-induced expression of IL. Sci Immunol. 2017;2:eaal3062.
   PubMed Web of Science ®Google Scholar
• Suzuki A, Yamada R, Chang X, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003;34:395–402.
   PubMed Web of Science ®Google Scholar
• Kang CP, Lee HS, Ju H, et al. A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum. 2006;54:90–96.
   PubMed Web of Science ®Google Scholar
• Denny MF, Yalavarthi S, Zhao W, et al. A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J Immunol. 2010;184:3284–3297.
   PubMed Web of Science ®Google Scholar
• Pieterse E, Hofstra J, Berden J, et al. Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus. Clin Exp Immunol. 2015;179:68–74.
   PubMed Web of Science ®Google Scholar
• Carestia A, Frechtel G, Cerrone G, et al. NETosis before and after hyperglycemic control in type 2 diabetes mellitus patients. PLoS One. 2016;11:e0168647.
   PubMedGoogle Scholar
• Wong SL, Demers M, Martinod K, et al. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med. 2015;21:815–819.
   PubMed Web of Science ®Google Scholar
• Wang Y, Xiao Y, Zhong L, et al. Increased neutrophil elastase and proteinase 3 and augmented NETosis are closely associated with beta-cell autoimmunity in patients with type 1 diabetes. Diabetes. 2014;63:4239–4248.
   PubMed Web of Science ®Google Scholar
• Valle A, Giamporcaro GM, Scavini M, et al. Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. Diabetes. 2013;62:2072–2077.
   PubMed Web of Science ®Google Scholar
• Knight JS, Zhao W, Luo W, et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J Clin Invest. 2013;123:2981–2993.
   PubMed Web of Science ®Google Scholar
• Knight JS, Subramanian V, O'Dell AA, et al. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann Rheum Dis. 2015;74:2199–2206.
   PubMed Web of Science ®Google Scholar
• Campbell AM, Kashgarian M, Shlomchik MJ. NADPH oxidase inhibits the pathogenesis of systemic lupus erythematosus. Sci Transl Med. 2012;4:157ra141.
   PubMed Web of Science ®Google Scholar
• Jacob CO, Yu N, Yoo DG, et al. Haploinsufficiency of NADPH oxidase subunit neutrophil cytosolic factor 2 is sufficient to accelerate full-blown lupus in NZM 2328 mice. Arthritis Rheumatol. 2017;69:1647–1660.
   PubMed Web of Science ®Google Scholar
• Caielli S, Athale S, Domic B, et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med. 2016;213:697–713.
   PubMed Web of Science ®Google Scholar
• Lood C, Blanco LP, Purmalek MM, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22:146–153.
   PubMed Web of Science ®Google Scholar
• Wang Y, Wysocka J, Sayegh J, et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science. 2004;306:279–283.
   PubMed Web of Science ®Google Scholar
• Cuthbert GL, Daujat S, Snowden AW, et al. Histone deimination antagonizes arginine methylation. Cell. 2004;118:545–553.
   PubMed Web of Science ®Google Scholar
• Zhang X, Gamble MJ, Stadler S, et al. Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells. PLoS Genet. 2011;7:e1002112.
   PubMed Web of Science ®Google Scholar
• Kolodziej S, Kuvardina ON, Oellerich T, et al. PADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation. Nat Commun. 2014;5:3995.
   PubMed Web of Science ®Google Scholar
• Stadler SC, Vincent CT, Fedorov VD, et al. Dysregulation of PAD4-mediated citrullination of nuclear GSK3beta activates TGF-beta signaling and induces epithelial-to-mesenchymal transition in breast cancer cells. Proc Natl Acad Sci USA. 2013;110:11851–11856.
   PubMed Web of Science ®Google Scholar
• Li P, Wang D, Yao H, et al. Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression. Oncogene. 2010;29:3153–3162.
   PubMed Web of Science ®Google Scholar
• Christophorou MA, Castelo-Branco G, Halley-Stott RP, et al. Citrullination regulates pluripotency and histone H1 binding to chromatin. Nature. 2014;507:104–108.
   PubMed Web of Science ®Google Scholar
• Guertin MJ, Zhang X, Anguish L, et al. Targeted H3R26 deimination specifically facilitates estrogen receptor binding by modifying nucleosome structure. PLoS Genet. 2014;10:e1004613.
   PubMed Web of Science ®Google Scholar
• Kenny EF, Herzig A, Kruger R, et al. Diverse stimuli engage different neutrophil extracellular trap pathways. eLife. 2017;6:e24437.
   PubMed Web of Science ®Google Scholar
• Leshner M, Wang S, Lewis C, et al. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Front Immun. 2012;3:307.
   PubMed Web of Science ®Google Scholar
• Khan MA, Palaniyar N. Transcriptional firing helps to drive NETosis. Sci Rep. 2017;7:41749.
   PubMed Web of Science ®Google Scholar
• Senshu T, Akiyama K, Kan S, et al. Detection of deiminated proteins in rat skin: probing with a monospecific antibody after modification of citrulline residues. J Investig Dermatol. 1995;105:163–169.
   PubMed Web of Science ®Google Scholar
• Lewallen DM, Bicker KL, Subramanian V, et al. Chemical proteomic platform to identify citrullinated proteins. ACS Chem Biol. 2015;10:2520–2528.
   PubMed Web of Science ®Google Scholar
• Tutturen AE, Fleckenstein B, de Souza GA. Assessing the citrullinome in rheumatoid arthritis synovial fluid with and without enrichment of citrullinated peptides. J Proteome Res. 2014;13:2867–2873.
   PubMed Web of Science ®Google Scholar
• Struyf S, Noppen S, Loos T, et al. Citrullination of CXCL12 differentially reduces CXCR4 and CXCR7 binding with loss of inflammatory and anti-HIV-1 activity via CXCR4. J Immunol. 2009;182:666–674.
   PubMed Web of Science ®Google Scholar
• Proost P, Loos T, Mortier A, et al. Citrullination of CXCL8 by peptidylarginine deiminase alters receptor usage, prevents proteolysis, and dampens tissue inflammation. J Exp Med. 2008;205:2085–2097.
   PubMed Web of Science ®Google Scholar
• Gordon RA, Herter JM, Rosetti F, et al. Lupus and proliferative nephritis are PAD4 independent in murine models. JCI Insight. 2017;2(10):e92920.
   PubMed Web of Science ®Google Scholar
• Tsuboi N, Asano K, Lauterbach M, et al. Human neutrophil Fcgamma receptors initiate and play specialized nonredundant roles in antibody-mediated inflammatory diseases. Immunity 2008;28:833–846.
   PubMed Web of Science ®Google Scholar
• Li H, Han SJ, Kim M, et al. Divergent roles for kidney proximal tubule and granulocyte PAD4 in ischemic AKI. Am J Physiol. Renal Physiol. 2018;314:F809–F819.
   PubMed Web of Science ®Google Scholar
• Biron BM, Chung CS, O'Brien XM, et al. Cl-Amidine prevents histone 3 citrullination and neutrophil extracellular trap formation, and improves survival in a murine sepsis model. J Innate Immun. 2017;9:22–32.
   PubMed Web of Science ®Google Scholar
• Kienhofer D, Hahn J, Stoof J, et al. Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. JCI Insight. 2017;2(10):e92920.
   PubMed Web of Science ®Google Scholar
• Schauer C, Janko C, Munoz LE, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 2014;20:511–517.
   PubMed Web of Science ®Google Scholar
• Liu CL, Tangsombatvisit S, Rosenberg JM, et al. Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies. Arthritis Res Ther. 2012;14:403.
   Web of Science ®Google Scholar
• Mevorach D, Zhou JL, Song X, et al. Systemic exposure to irradiated apoptotic cells induces autoantibody production. J Exp Med. 1998;188:387–392.
   PubMed Web of Science ®Google Scholar
• Ireland JM, Unanue ER. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J Exp Med. 2011;208:2625–2632.
   PubMed Web of Science ®Google Scholar
• Dwivedi N, Hedberg A, Zheng YY, et al. B cell tolerance to deiminated histones in BALB/c, C57BL/6, and autoimmune-prone mouse strains. Front Immunol. 2017;8:362.
   PubMed Web of Science ®Google Scholar
• Farrera C, Fadeel B. Macrophage clearance of neutrophil extracellular traps is a silent process. J Immunol. 2013;191:2647–2656.
   PubMed Web of Science ®Google Scholar
• Wong A, D, Bryzek E, Dobosz C, et al. A novel biological role for peptidyl-arginine deiminases: citrullination of cathelicidin LL-37 controls the immunostimulatory potential of cell-free DNA. J Immunol. 2018;200:2327–2340.
   PubMed Web of Science ®Google Scholar
• Dwivedi N, Upadhyay J, Neeli I, et al. Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps. Arthritis Rheumatism. 2012;64:982–992.
   Web of Science ®Google Scholar
• Soderberg D, Segelmark M. Neutrophil extracellular traps in ANCA-associated vasculitis. Front Immunol. 2016;7:256.
   PubMed Web of Science ®Google Scholar
• Carmona-Rivera C, Carlucci PM, Moore E, et al. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol. 2017;2:eaag3358.
   PubMed Web of Science ®Google Scholar
• Farquharson D, Butcher JP, Culshaw S. Periodontitis, porphyromonas, and the pathogenesis of rheumatoid arthritis. Mucosal Immunol. 2012;5:112–120.
   PubMed Web of Science ®Google Scholar
• Goulas T, Mizgalska D, Garcia-Ferrer I, et al. Structure and mechanism of a bacterial host-protein citrullinating virulence factor, Porphyromonas gingivalis peptidylarginine deiminase. Sci Rep. 2015;5:11969.
   PubMed Web of Science ®Google Scholar
• Konig MF, Abusleme L, Reinholdt J, et al. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci Transl Med. 2016;8:369ra176.
   PubMed Web of Science ®Google Scholar