Skip to main content
Top

21-06-2018 | Pathogenesis | Review | Article

The role of neutrophil extracellular traps in rheumatic diseases

Journal: Nature Reviews Rheumatology

Authors: Falko Apel, Arturo Zychlinsky, Elaine F. Kenny

Publisher: Nature Publishing Group UK

Abstract

Rheumatic diseases are a collection of disorders defined by the presence of inflammation and destruction of joints and internal organs. A common feature of these diseases is the presence of autoantibodies targeting molecules commonly expressed in neutrophils. These preformed mediators are released by neutrophils but not by other immune cells such as macrophages. Neutrophils, major players in the host innate immune response, initiate a cell death mechanism termed neutrophil extracellular trap (NET) formation as a way to ensnare pathogens. NETs are also a source of released self-molecules found in rheumatic diseases. Subsequently, research on the role of NETs in the onset, progression and resolution of inflammation in rheumatic diseases has intensified. This Review has two aims. First, it aims to highlight the mechanisms required for the generation of NETs, the research landscape of which is rapidly changing. Second, it aims to discuss the role of neutrophils and NETs in systemic lupus erythematosus, vasculitis (specifically anti-neutrophil cytoplasmic autoantibody-associated vasculitis), rheumatoid arthritis and gout. Our goal is to clarify the field of NET research in rheumatic diseases in the hope of improving the therapeutic approaches utilized for these diseases.
Literature
1.
Goldblatt, F. & O’Neill, S. G. Clinical aspects of autoimmune rheumatic diseases. Lancet 382, 797–808 (2006).CrossRef
2.
Diamond, B., Bluestone, J. & Wofsy, D. The immune tolerance network and rheumatic disease: immune tolerance comes to the clinic. Arthritis Rheum. 44, 1730–1735 (2001).PubMedCrossRef
3.
Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).PubMedCrossRef
4.
Gupta, S. & Kaplan, M. J. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat. Rev. Nephrol. 12, 402–413 (2016).PubMedCrossRefPubMedCentral
5.
Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).PubMedCrossRef
6.
Borregaard, N. Neutrophils, from marrow to microbes. Immunity 33, 657–670 (2010).PubMedCrossRef
7.
Amulic, B., Cazalet, C., Hayes, G. L., Metzler, K. D. & Zychlinsky, A. Neutrophil function: from mechanisms to disease. Annu. Rev. Immunol. 30, 459–489 (2012).PubMedCrossRef
8.
Tak, T., Tesselaar, K., Pillay, J., Borghans, J. A. M. & Koenderman, L. What’s your age again? Determination of human neutrophil half-lives revisited. J. Leukoc. Biol. 94, 595–601 (2013).PubMedCrossRef
9.
Tecchio, C., Micheletti, A. & Cassatella, M. A. Neutrophil-derived cytokines: facts beyond expression. Front. Immunol. 5, 508 (2014).PubMedCrossRefPubMedCentral
10.
Mantovani, A., Cassatella, M. A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 11, 519–531 (2011).PubMedCrossRef
11.
Kenny, E. F. et al. Diverse stimuli engage different neutrophil extracellular trap pathways. eLife 6, e24437 (2017).PubMedCrossRefPubMedCentral
12.
Papayannopoulos, V., Metzler, K. D., Hakkim, A. & Zychlinsky, A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J. Cell Biol. 191, 677–691 (2010).PubMedCrossRefPubMedCentral
13.
Metzler, K. D., Goosmann, C., Lubojemska, A., Zychlinsky, A. & Papayannopoulos, V. A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis. Cell Rep. 8, 883–896 (2014).PubMedCrossRefPubMedCentral
14.
Amulic, B. et al. Cell-cycle proteins control production of neutrophil extracellular traps. Dev. Cell 43, 449–462 (2017).PubMedCrossRef
15.
Martinod, K. et al. Neutrophil elastase-deficient mice form neutrophil extracellular traps in an experimental model of deep vein thrombosis. J. Thromb. Haemost. 14, 551–558 (2016).PubMedCrossRefPubMedCentral
16.
Bruhns, P. Properties of mouse and human IgG receptors and their contribution to disease models. Blood 119, 5640–5649 (2012).PubMedCrossRef
17.
Kaplan, M. J. & Radic, M. Neutrophil extracellular traps: double-edged swords of innate immunity. J. Immunol. 189, 2689–2695 (2012).PubMedCrossRef
18.
Bryan, N. et al. Reactive oxygen species (ROS) — a family of fate deciding molecules pivotal in constructive inflammation and wound healing. Eur. Cell. Mater. 24, 249–265 (2012).PubMedCrossRef
19.
Hirsch, J. G. Bactericidal action of histone. J. Exp. Med. 108, 925–944 (1958).PubMedCrossRefPubMedCentral
20.
Lee, J. J. & Pope, J. E. A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases. Arthritis Res. Ther. 16, 435 (2014).PubMedCrossRefPubMedCentral
21.
Rahman, A. & Isenberg, D. A. Systemic lupus erythematosus. N. Engl. J. Med. 358, 929–939 (2008).PubMedCrossRef
22.
Wilhelm, A. J. & Major, A. S. Accelerated atherosclerosis in SLE: mechanisms and prevention approaches. Int. J. Clin. Rheumtol. 7, 527–539 (2012).PubMedCrossRefPubMedCentral
23.
Stojan, G. & Petri, M. Atherosclerosis in systemic lupus erythematosus. J. Cardiovasc. Pharmacol. 62, 255–262 (2013).PubMedCrossRefPubMedCentral
24.
Anders, H.-J. J. & Vielhauer, V. Renal co-morbidity in patients with rheumatic diseases. Arthritis Res. Ther. 13, 222 (2011).PubMedCrossRefPubMedCentral
25.
Hargraves, M. M., Richmond, H. & Morton, R. Presentation of two bone marrow elements; the tart cell and the L. E. cell. Proc. Staff Meet. Mayo Clin. 23, 25–28 (1948).PubMed
26.
Carli, L., Tani, C., Vagnani, S., Signorini, V. & Mosca, M. Leukopenia, lymphopenia, and neutropenia in systemic lupus erythematosus: prevalence and clinical impact — a systematic literature review. Semin. Arthritis Rheum. 45, 190–194 (2015).PubMedCrossRef
27.
Hakkim, A. et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc. Natl Acad. Sci. USA 107, 9813–9818 (2010).PubMedCrossRefPubMedCentral
28.
Villanueva, E. et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187, 538–552 (2011).PubMedCrossRef
29.
Wang, H., Li, T., Chen, S., Gu, Y. & Ye, S. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol. 67, 3190–3200 (2015).PubMedCrossRef
30.
Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra19 (2011).PubMedCrossRefPubMedCentral
31.
Garcia-Romo, G. S. et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 (2011).PubMedCrossRefPubMedCentral
32.
Arandjelovic, S. & Ravichandran, K. S. Phagocytosis of apoptotic cells in homeostasis. Nat. Immunol. 16, 907–917 (2015).PubMedCrossRefPubMedCentral
33.
Farrera, C. & Fadeel, B. Macrophage clearance of neutrophil extracellular traps is a silent process. J. Immunol. 191, 2647–2656 (2013).PubMedCrossRef
34.
Ren, Y. et al. Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. Arthritis Rheum. 48, 2888–2897 (2003).PubMedCrossRef
35.
Shao, W.-H. H. & Cohen, P. L. Disturbances of apoptotic cell clearance in systemic lupus erythematosus. Arthritis Res. Ther. 13, 202 (2011).PubMedCrossRefPubMedCentral
36.
Midgley, A. & Beresford, M. W. Cellular localization of nuclear antigen during neutrophil apoptosis: mechanism for autoantigen exposure? Lupus 20, 641–646 (2011).PubMedCrossRef
37.
Leffler, J. et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J. Immunol. 188, 3522–3531 (2012).PubMedCrossRef
38.
Fang, Y., Xu, C., Fu, Y. X., Holers, V. M. & Molina, H. Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. J. Immunol. 160, 5273–5279 (1998).PubMed
39.
Maletto, B. A. et al. Presence of neutrophil-bearing antigen in lymphoid organs of immune mice. Blood 108, 3094–3102 (2006).PubMedCrossRef
40.
Duffy, D. et al. Neutrophils transport antigen from the dermis to the bone marrow, initiating a source of memory CD8+ T Cells. Immunity 37, 917–929 (2012).PubMedCrossRef
41.
Abi Abdallah, D. S., Egan, C. E., Butcher, B. A. & Denkers, E. Y. Mouse neutrophils are professional antigen-presenting cells programmed to instruct Th1 and Th17 T cell differentiation. Int. Immunol. 23, 317–326 (2011).PubMedCrossRefPubMedCentral
42.
Friou, G. J. Clinical application of a test for lupus globulin-nucleohistone interaction using fluorescent antibody. Yale J. Biol. Med. 31, 40–47 (1958).PubMedPubMedCentral
43.
Fritzler, M. J. & Tan, E. M. Antibodies to histones in drug-induced and idiopathic lupus erythematosus. J. Clin. Invest. 62, 560–567 (1978).PubMedCrossRefPubMedCentral
44.
Nässberger, L., Jonsson, H., Sjöholm, A. G., Sturfelt, G. & Heubner, A. Circulating anti-elastase in systemic lupus erythematosus. Lancet 1, 509 (1989).PubMedCrossRef
45.
Spronk, P. E. et al. Antineutrophil cytoplasmic antibodies in systemic lupus erythematosus. Br. J. Rheumatol. 35, 625–631 (1996).PubMedCrossRef
46.
Cervera, R. et al. Anti-chromatin antibodies in systemic lupus erythematosus: a useful marker for lupus nephropathy. Ann. Rheum. Dis. 62, 431–434 (2003).PubMedCrossRefPubMedCentral
47.
Carmona-Rivera, C., Zhao, W., Yalavarthi, S. & Kaplan, M. J. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann. Rheum. Dis. 74, 1417–1424 (2015).PubMedCrossRef
48.
Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016).PubMedCrossRefPubMedCentral
49.
Hirose, O., Itabashi, M., Takei, T., Honda, K. & Nitta, K. Antineutrophil cytoplasmic antibody-associated glomerulonephritis with immunoglobulin deposition. Clin. Exp. Nephrol. 21, 643–650 (2017).PubMedCrossRef
50.
Skiljevic, D. et al. Serum DNase I activity in systemic lupus erythematosus: correlation with immunoserological markers, the disease activity and organ involvement. Clin. Chem. Lab. Med. 51, 1083–1091 (2013).PubMedCrossRef
51.
Bodaño, A., Amarelo, J., González, A., Gómez-Reino, J. J. & Conde, C. Novel DNASE I mutations related to systemic lupus erythematosus. Arthritis Rheum. 50, 4070–4071 (2004).PubMedCrossRef
52.
Al-Mayouf, S. M. et al. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat. Genet. 43, 1186–1188 (2011).PubMedCrossRef
53.
Napirei, M. et al. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat. Genet. 25, 177–181 (2000).PubMedCrossRef
54.
Sisirak, V. et al. Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell 166, 88–101 (2016).PubMedCrossRefPubMedCentral
55.
Gehrke, N. et al. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39, 482–495 (2013).PubMedCrossRef
56.
Frost, P. G. & Lachmann, P. J. The relationship of desoxyribonuclease inhibitor levels in human sera to the occurrence of antinuclear antibodies. Clin. Exp. Immunol. 3, 447–455 (1968).PubMedPubMedCentral
57.
Yeh, T.-M. M., Chang, H.-C. C., Liang, C.-C. C., Wu, J.-J. J. & Liu, M.-F. F. Deoxyribonuclease-inhibitory antibodies in systemic lupus erythematosus. J. Biomed. Sci. 10, 544–551 (2003).PubMedCrossRef
58.
Trofimenko, A. S., Gontar, I. P., Zborovsky, A. B. & Paramonova, O. V. Anti-DNase I antibodies in systemic lupus erythematosus: diagnostic value and share in the enzyme inhibition. Rheumatol. Int. 36, 521–529 (2016).PubMedCrossRef
59.
Hooks, J. J. et al. Immune interferon in the circulation of patients with autoimmune disease. N. Engl. J. Med. 301, 5–8 (1979).PubMedCrossRef
60.
Preble, O. T., Black, R. J., Friedman, R. M., Klippel, J. H. & Vilcek, J. Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon. Science 216, 429–431 (1982).PubMedCrossRef
61.
Banchereau, J. & Pascual, V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25, 383–392 (2006).PubMedCrossRef
62.
Crow, M. K. Type I interferon in the pathogenesis of lupus. J. Immunol. 192, 5459–5468 (2014).PubMedCrossRef
63.
Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).PubMedCrossRef
64.
Caielli, S. et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J. Exp. Med. 213, 697–713 (2016).PubMedCrossRefPubMedCentral
65.
Lartigue, A. et al. Role of TLR9 in anti-nucleosome and anti-DNA antibody production in lpr mutation-induced murine lupus. J. Immunol. 177, 1349–1354 (2006).PubMedCrossRef
66.
Nickerson, K. M., Cullen, J. L., Kashgarian, M. & Shlomchik, M. J. Exacerbated autoimmunity in the absence of TLR9 in MRL. Fas(lpr) mice depends on Ifnar1. J. Immunol. 190, 3889–3894 (2013).PubMedCrossRef
67.
Kahlenberg, J. M., Carmona-Rivera, C., Smith, C. K. & Kaplan, M. J. Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J. Immunol. 190, 1217–1226 (2013).PubMedCrossRef
68.
Denny, M. F. 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. 184, 3284–3297 (2010).PubMedCrossRef
69.
Hacbarth, E. & Kajdacsy-Balla, A. Low density neutrophils in patients with systemic lupus erythematosus, rheumatoid arthritis, and acute rheumatic fever. Arthritis Rheum. 29, 1334–1342 (1986).PubMedCrossRef
70.
Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).PubMedCrossRefPubMedCentral
71.
Midgley, A. & Beresford, M. W. Increased expression of low density granulocytes in juvenile-onset systemic lupus erythematosus patients correlates with disease activity. Lupus 25, 407–411 (2016).PubMedCrossRef
72.
Macanovic, M. et al. The treatment of systemic lupus erythematosus (SLE) in NZB/W F1 hybrid mice; studies with recombinant murine DNase and with dexamethasone. Clin. Exp. Immunol. 106, 243–252 (1996).PubMedCrossRefPubMedCentral
73.
Davis, J. C. et al. Recombinant human Dnase I (rhDNase) in patients with lupus nephritis. Lupus 8, 68–76 (1999).PubMedCrossRef
74.
Winkelstein, J. A. et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine 79, 155–169 (2000).PubMedCrossRef
75.
Campbell, A. M., Kashgarian, M. & Shlomchik, M. J. NADPH oxidase inhibits the pathogenesis of systemic lupus erythematosus. Sci. Transl. Med. 4, 157ra141 (2012).PubMedCrossRefPubMedCentral
76.
Jacob, C. O. et al. Haploinsufficiency of NADPH oxidase subunit neutrophil cytosolic factor 2 is sufficient to accelerate full-blown lupus in NZM 2328 mice. Arthritis Rheumatol. 69, 1647–1660 (2017).PubMedCrossRef
77.
Kienhöfer, D. et al. Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. JCI insight 2, 92920 (2017).PubMedCrossRef
78.
Knight, J. S. et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J. Clin. Invest. 123, 2981–2993 (2013).PubMedCrossRefPubMedCentral
79.
Knight, J. S. 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. 74, 2199–2206 (2015).PubMedCrossRef
80.
Gordon, R. A. et al. Lupus and proliferative nephritis are PAD4 independent in murine models. JCI insight 2, e92926 (2017).CrossRefPubMedCentral
81.
Elefante, E. et al. One year in review 2017: systemic vasculitis. Clin. Exp. Rheumatol. 35 (Suppl. 1), 5–26 (2017).PubMed
82.
Kallenberg, C. G. M., Heeringa, P. & Stegeman, C. A. Mechanisms of disease: pathogenesis and treatment of ANCA-associated vasculitides. Nat. Rev. Rheumatol. 2, 661–670 (2006).CrossRef
83.
Muñoz-Grajales, C. & Pineda, J. C. Pathophysiological relationship between infections and systemic vasculitis. Autoimmune Dis. 2015, 1–8 (2015).CrossRef
84.
Jennette, J. C. & Falk, R. J. Small-vessel vasculitis. N. Engl. J. Med. 337, 1512–1523 (1997).PubMedCrossRef
85.
Söderberg, D. & Segelmark, M. Neutrophil extracellular traps in ANCA-Associated vasculitis. Front. Immunol. 7, 256 (2016).PubMedCrossRefPubMedCentral
86.
Falk, R. J. & Jennette, J. C. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N. Engl. J. Med. 318, 1651–1657 (1988).PubMedCrossRef
87.
Niles, J. L., McCluskey, R. T., Ahmad, M. F. & Arnaout, M. A. Wegener’s granulomatosis autoantigen is a novel neutrophil serine proteinase. Blood 74, 1888–1893 (1989).PubMed
88.
Charles, L. A., Caldas, M. L., Falk, R. J., Terrell, R. S. & Jennette, J. C. Antibodies against granule proteins activate neutrophils in vitro. J. Leukoc. Biol. 50, 539–546 (1991).PubMedCrossRef
89.
Brogan, P. & Eleftheriou, D. Vasculitis update: pathogenesis and biomarkers. Pediatr. Nephrol. 33, 187–198 (2017).PubMedCrossRefPubMedCentral
90.
Falk, R. J., Terrell, R. S., Charles, L. A. & Jennette, J. C. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc. Natl Acad. Sci. USA 87, 4115–4119 (1990).PubMedCrossRefPubMedCentral
91.
Kessenbrock, K. et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat. Med. 15, 623–625 (2009).PubMedCrossRefPubMedCentral
92.
Söderberg, D. et al. Increased levels of neutrophil extracellular trap remnants in the circulation of patients with small vessel vasculitis, but an inverse correlation to anti-neutrophil cytoplasmic antibodies during remission. Rheumatology 54, 2085–2094 (2015).PubMedCrossRef
93.
Cheadle, C. et al. Transcription of proteinase 3 and related myelopoiesis genes in peripheral blood mononuclear cells of patients with active Wegener’s granulomatosis. Arthritis Rheum. 62, 1744–1754 (2010).PubMedCrossRefPubMedCentral
94.
Lyons, P. A. et al. Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis. Ann. Rheum. Dis. 69, 1208–1213 (2010).PubMedCrossRef
95.
Grayson, P. C. et al. Neutrophil-related gene expression and low-density granulocytes associated with disease activity and response to treatment in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol. 67, 1922–1932 (2015).PubMedCrossRefPubMedCentral
96.
Sangaletti, S. et al. Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood 120, 3007–3018 (2012).PubMedCrossRef
97.
Kumar, S. V. et al. Neutrophil extracellular trap-related extracellular histones cause vascular necrosis in severe GN. J. Am. Soc. Nephrol. 26, 2399–2413 (2015).PubMedCrossRefPubMedCentral
98.
Kusunoki, Y. et al. Peptidylarginine deiminase inhibitor suppresses neutrophil extracellular trap formation and MPO-ANCA production. Front. Immunol. 7, 227 (2016).PubMedCrossRefPubMedCentral
99.
Jiménez-Alcázar, M. et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science 358, 1202–1206 (2017).PubMedCrossRef
100.
Deane, K. D. Preclinical rheumatoid arthritis (autoantibodies): an updated review. Curr. Rheumatol. Rep. 16, 419 (2014).PubMedCrossRefPubMedCentral
101.
Chaudhari, K., Rizvi, S. & Syed, B. A. Rheumatoid arthritis: current and future trends. Nat. Rev. Drug Discov. 15, 305–306 (2016).PubMedCrossRef
102.
Smolen, J. S., Aletaha, D. & McInnes, I. B. Rheumatoid arthritis. Lancet 388, 2023–2038 (2016).PubMedCrossRef
103.
Angelotti, F. et al. One year in review 2017: pathogenesis of rheumatoid arthritis. Clin. Exp. Rheumatol. 35, 368–378 (2017).PubMed
104.
Edwards, S. W. & Hallett, M. B. Seeing the wood for the trees: the forgotten role of neutrophils in rheumatoid arthritis. Immunol. Today 18, 320–324 (1997).PubMedCrossRef
105.
Ottonello, L. et al. Delayed neutrophil apoptosis induced by synovial fluid in rheumatoid arthritis: role of cytokines, estrogens, and adenosine. Ann. N. Y Acad. Sci. 966, 226–231 (2002).PubMedCrossRef
106.
Eggleton, P., Wang, L., Penhallow, J., Crawford, N. & Brown, K. A. Differences in oxidative response of subpopulations of neutrophils from healthy subjects and patients with rheumatoid arthritis. Ann. Rheum. Dis. 54, 916–923 (1995).PubMedCrossRefPubMedCentral
107.
Corsiero, E., Pratesi, F., Prediletto, E., Bombardieri, M. & Migliorini, P. NETosis as source of autoantigens in rheumatoid arthritis. Front. Immunol. 7, 485 (2016).PubMedPubMedCentral
108.
Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl. Med. 5, 178ra40 (2013).PubMedCrossRefPubMedCentral
109.
Wegner, N. et al. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol. Rev. 233, 34–54 (2010).PubMedCrossRef
110.
Carmona-Rivera, C. et al. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci. Immunol. 2, eaag3358 (2017).PubMedCrossRefPubMedCentral
111.
Wright, H. L., Makki, F. A., Moots, R. J. & Edwards, S. W. Low-density granulocytes: functionally distinct, immature neutrophils in rheumatoid arthritis with altered properties and defective TNF signalling. J. Leukoc. Biol. 101, 599–611 (2017).PubMedCrossRef
112.
Kouskoff, V. et al. Organ-specific disease provoked by systemic autoimmunity. Cell 87, 811–822 (1996).PubMedCrossRef
113.
Korganow, A. S. et al. From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 10, 451–461 (1999).PubMedCrossRef
114.
Ji, H. et al. Genetic influences on the end-stage effector phase of arthritis. J. Exp. Med. 194, 321–330 (2001).PubMedCrossRefPubMedCentral
115.
Wipke, B. T. & Allen, P. M. Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J. Immunol. 167, 1601–1608 (2001).PubMedCrossRef
116.
Christensen, A. D., Haase, C., Cook, A. D. & Hamilton, J. A. K/BxN serum-transfer arthritis as a model for human inflammatory arthritis. Front. Immunol. 7, 213 (2016).PubMedCrossRefPubMedCentral
117.
Karsunky, H. et al. Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nat. Genet. 30, 295–300 (2002).PubMedCrossRef
118.
Monach, P. A. et al. Neutrophils in a mouse model of autoantibody-mediated arthritis: critical producers of Fc receptor gamma, the receptor for C5a, and lymphocyte function-associated antigen 1. Arthritis Rheum. 62, 753–764 (2010).PubMedCrossRefPubMedCentral
119.
Maicas, N. et al. Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxid. Redox Signal. 15, 889–901 (2011).PubMedCrossRef
120.
Rohrbach, A. S., Hemmers, S., Arandjelovic, S., Corr, M. & Mowen, K. A. PAD4 is not essential for disease in the K/BxN murine autoantibody-mediated model of arthritis. Arthritis Res. Ther. 14, R104 (2012).PubMedCrossRefPubMedCentral
121.
Owlia, M. B., Newman, K. & Akhtari, M. Felty’s syndrome, insights and updates. Open Rheumatol. J. 8, 129–136 (2014).PubMedCrossRefPubMedCentral
122.
Dwivedi, N. & Radic, M. Citrullination of autoantigens implicates NETosis in the induction of autoimmunity. Ann. Rheum. Dis. 73, 483–491 (2014).PubMedCrossRef
123.
Nuki, G. & Simkin, P. A. A concise history of gout and hyperuricemia and their treatment. Arthritis Res. Ther. 8, S1 (2006).PubMedCrossRefPubMedCentral
124.
Malawista, S. E., de Boisfleury, A. C. & Naccache, P. H. Inflammatory gout: observations over a half-century. FASEB J. 25, 4073–4078 (2011).PubMedCrossRefPubMedCentral
125.
Kuo, C.-F., Grainge, M. J., Mallen, C., Zhang, W. & Doherty, M. Comorbidities in patients with gout prior to and following diagnosis: case-control study. Ann. Rheum. Dis. 75, 210–217 (2014).PubMedCrossRef
126.
Kuo, C.-F., Grainge, M. J., Zhang, W. & Doherty, M. Global epidemiology of gout: prevalence, incidence and risk factors. Nat. Rev. Rheumatol. 11, 649–662 (2015).PubMedCrossRef
127.
Rada, B. Neutrophil extracellular traps and microcrystals. J. Immunol. Res. 2017, 1–7 (2017).CrossRef
128.
Amaral, F. A. A. et al. NLRP3 inflammasome-mediated neutrophil recruitment and hypernociception depend on leukotriene B(4) in a murine model of gout. Arthritis Rheum. 64, 474–484 (2012).PubMedCrossRef
129.
Mitroulis, I., Kambas, K. & Ritis, K. Neutrophils, IL-1β, and gout: is there a link? Semin. Immunopathol. 35, 501–512 (2013).PubMedCrossRef
130.
Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A. & Nature, T.-J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).PubMedCrossRef
131.
Ryckman, C. et al. Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis. Arthritis Rheum. 48, 2310–2320 (2003).PubMedCrossRef
132.
Popa-Nita, O. & Naccache, P. H. Crystal-induced neutrophil activation. Immunol. Cell Biol. 88, 32–40 (2010).PubMedCrossRef
133.
Mitroulis, I. et al. Neutrophil extracellular trap formation is associated with IL-1β and autophagy-related signaling in gout. PLoS ONE 6, e29318 (2011).PubMedCrossRefPubMedCentral
134.
Schauer, C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014).PubMedCrossRef
135.
Chatfield, S. M. et al. Monosodium urate crystals generate nuclease-resistant neutrophil extracellular traps via a distinct molecular pathway. J. Immunol. 200, 1802–1816 (2018).PubMed
136.
Chhana, A. & Dalbeth, N. The gouty tophus: a review. Curr. Rheumatol. Rep. 17, 19 (2015).PubMedCrossRef
137.
Reber, L. L., Gaudenzio, N., Starkl, P. & Galli, S. J. Neutrophils are not required for resolution of acute gouty arthritis in mice. Nat. Med. 22, 1382–1384 (2016).PubMedCrossRef
138.
Clain, J. M., Cartin-Ceba, R., Fervenza, F. C. & Specks, U. Experience with rituximab in the treatment of antineutrophil cytoplasmic antibody associated vasculitis. Ther. Adv. Musculoskelet. Dis. 6, 58–74 (2013).CrossRef
139.
Mok, C. C. Current role of rituximab in systemic lupus erythematosus. Int. J. Rheum. Dis. 18, 154–163 (2015).PubMedCrossRef
140.
Flossmann, O. et al. Long-term patient survival in ANCA-associated vasculitis. Ann. Rheum. Dis. 70, 488–494 (2011).PubMedCrossRef
141.
Ragab, G., Elshahaly, M. & Bardin, T. Gout: an old disease in new perspective – a review. J. Adv. Res. 8, 495–511 (2017).PubMedCrossRefPubMedCentral
142.
Willis, V. C. et al. N-Α-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis. J. Immunol. 186, 4396–4404 (2011).PubMedCrossRef
143.
McDonald, B., Urrutia, R., Yipp, B. G., Jenne, C. N. & Kubes, P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 12, 324–333 (2012).PubMedCrossRef
144.
Kolaczkowska, E. et al. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nat. Commun. 6, 6673 (2015).PubMedCrossRef
145.
Brinkmann, V., Abu Abed, U., Goosmann, C. & Zychlinsky, A. Immunodetection of NETs in paraffin-embedded tissue. Front. Immunol. 7, 513 (2016).PubMedCrossRefPubMedCentral
146.
Papayannopoulos, V., Staab, D. & Zychlinsky, A. Neutrophil elastase enhances sputum solubilization in cystic fibrosis patients receiving DNase therapy. PLoS ONE 6, e28526 (2011).PubMedCrossRefPubMedCentral
147.
Caudrillier, A. et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J. Clin. Invest. 122, 2661–2671 (2012).PubMedCrossRefPubMedCentral