"The NET Outcome": Are Neutrophil Extracellular Traps of Any Relevance to the Pathophysiology of Autoimmune Disorders in Childhood?
Neutrophil extracellular trap (NET) formation represents a form of cell death distinct from apoptosis or necrosis, by which invading pathogens are simultaneously entangled and potentially eliminated. Increased NET formation is observed in systemic lupus erythematosus (SLE), rheumatoid arthritis, antineutrophil cytoplasmic antibody-associated small vessel vasculitis, antiphospholipid antibody syndrome (APS), and psoriasis. NETs contribute to the pathogenesis of autoimmunity by exposing cryptic autoepitopes, which may facilitate the generation of autoantibodies, induce the production of interferons, and activate the complement cascade. In SLE, augmented disease activity and renal disease are associated with increased NET formation, so that NETs could serve as a marker for the monitoring of disease activity. NETs can additionally cause endothelial cell damage and death and stimulate inflammation in atheromatous plaques, adding to the accelerated atherosclerosis witnessed in autoimmune disease. Since NETs induce production of interferons, assessing the extent of NET formation might facilitate the prediction of IFN-alpha levels and identification of SLE patients with presumably better responses to anti-IFN-alpha therapies or other novel therapeutic concepts, such as N-acetyl-cysteine and inhibitors of DNase 1 and peptidylarginine deiminase 4 (PAD4), which also target NETs. In summary, the study of NETs provides a novel approach to the understanding of autoimmune disease pathogenesis in childhood and opens new vistas in the development of sensitive disease markers and targeted therapies.
Laboratory of Prenantal Medicine, Department of Biomedicine, University Clinics Basel, Basel, Switzerland; Department of Rheumatology, Kantonsspital Aarau, Aarau, Switzerland.
Stavros
S
Giaglis
Laboratory of Prenantal Medicine, Department of Biomedicine, University Clinics Basel, Basel, Switzerland; University Women's Hospital, University Clinics Basel, Basel, Switzerland.
Sinuhe
S
Hahn
Department of Rheumatology, Kantonsspital Aarau , Aarau , Switzerland.
Paul
P
Hasler
NETosis; NETs; SLE; biomarkers; juvenile idiopathic arthritis; neutrophils
Nat Rev Rheumatol. 2011 Sep 27;7(12):691-9
21947176
J Immunol. 2011 Jul 1;187(1):538-52
21613614
Blood. 2011 Jan 20;117(3):953-9
20974672
Nat Med. 2010 Feb;16(2):219-23
20081861
Annu Rev Pathol. 2014;9:181-218
24050624
Nat Rev Immunol. 2006 Mar;6(3):173-82
16498448
Front Immunol. 2015 Apr 24;6:185
25999944
Trends Biochem Sci. 2011 Jan;36(1):30-8
20728362
J Immunol. 2008 Feb 1;180(3):1895-902
18209087
Nat Rev Microbiol. 2007 Aug;5(8):577-82
17632569
Sci Transl Med. 2011 Mar 9;3(73):73ra19
21389263
J Immunol. 2012 Apr 1;188(7):3522-31
22345666
Annu Rev Med. 2005;56:45-62
15660501
Acta Diabetol. 2015 Jun;52(3):497-503
25387570
Cell Rep. 2014 Aug 7;8(3):883-96
25066128
PLoS One. 2014 May 12;9(5):e97088
24819773
Clin Exp Immunol. 2014 Jul;177(1):134-41
24611519
J Allergy Clin Immunol. 2011 May;127(5):1243-52.e7
21376380
Semin Immunopathol. 2013 Jul;35(4):439-53
23649713
Clin Rheumatol. 2015 Jan;34(1):85-91
25344776
Nat Rev Rheumatol. 2009 Nov;5(11):616-26
19806151
Annu Rev Immunol. 2011;29:415-45
21219177
PLoS Pathog. 2009 Oct;5(10):e1000639
19876394
Arthritis Rheum. 2004 Dec;50(12):3762-71
15593206
Curr Opin Rheumatol. 2012 Sep;24(5):441-50
22617827
Nat Med. 2013 Jan;19(1):65-73
23242473
Ann Rheum Dis. 2015 Dec;74(12):2199-206
25104775
Nat Med. 2012 Sep;18(9):1407-12
22863787
Cell Adh Migr. 2016 Mar 3;10(1-2):208-25
26933824
Science. 2004 Mar 5;303(5663):1532-5
15001782
Sci Transl Med. 2013 Mar 27;5(178):178ra40
23536012
J Immunol Methods. 2015 Aug;423:104-10
26003624
J Thromb Haemost. 2015 Nov;13(11):2004-11
26333021
Drugs. 2015 May;75(8):835-46
25940912
Am J Pathol. 2009 Oct;175(4):1473-82
19729473
Diabetes. 2014 Dec;63(12 ):4172-85
25024373
Rheumatology (Oxford). 2014 Feb;53(2):270-4
24231443
Cell Res. 2011 Feb;21(2):290-304
21060338
J Rheumatol. 2004 Feb;31(2):390-2
14760812
Biomed Res Int. 2013;2013:542363
24175291
J Am Soc Nephrol. 2014 May;25(5):990-7
24385592
Arthritis Res Ther. 2014 Jun 13;16(3):R122
24928093
Nat Genet. 2013 Jun;45(6):664-9
23603761
Nat Rev Rheumatol. 2015 Aug;11(8):483-92
25963881
Arthritis Rheum. 2010 Nov;62(11):3265-76
20722033
Semin Immunopathol. 2013 Jul;35(4):455-63
23553215
Clin Exp Rheumatol. 2014 Jan-Feb;32(1):66-70
24295292
Nat Med. 2015 Jul;21(7):815-9
26076037
Immunobiology. 2016 Feb;221(2):208-19
26371849
Micron. 2008 Jun;39(4):367-72
17498964
J Leukoc Biol. 1996 Feb;59(2):229-40
8603995
J Cell Biol. 2012 Sep 3;198(5):773-83
22945932
J Cell Biol. 2010 Nov 1;191(3):677-91
20974816
Am J Hematol. 2015 Dec;90(12 ):1155-8
26347989
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9813-8
20439745
Nutrients. 2013 Aug 09;5(8):3131-51
23939536
Nat Commun. 2015 Mar 26;6:6673
25809117
Nat Rev Endocrinol. 2013 Feb;9(2):113-23
23296171
Arthritis Rheumatol. 2014 Feb;66(2):231-41
24504793
Nat Rev Immunol. 2011 Jul 25;11(8):519-31
21785456
Arthritis Res Ther. 2013 Aug 14;15(4):R84
23945056
J Immunol. 2012 Sep 15;189(6):2689-95
22956760
Autoimmun Rev. 2011 Jun;10(8):482-9
21320644
Nat Med. 2009 Jun;15(6):623-5
19448636
Diabetes. 2014 Dec;63(12):4239-48
25092677
Arthritis Res Ther. 2011 Jun 20;13(3):R95
21689402
Arthritis Res Ther. 2006;8(5):R154
17002793
Rheumatol Int. 2012 Oct;32(10):3285-90
21805174
Fetal Diagn Ther. 2016;40(4):263-267
26998969