KEGG   PATHWAY: epz04613
Entry
epz04613                    Pathway                                
Name
Neutrophil extracellular trap formation - Equus przewalskii (Przewalski's horse)
Description
Neutrophils play a central role in innate immune defense. One of the mechanisms of neutrophil action is the formation of neutrophil extracellular traps (NETs), the extracellular structures composed of chromatin coated with histones, proteases and granular and cytosolic proteins that help catch and kill microorganisms. NETs are formed by a process known as "NETosis" that can be triggered by microorganisms and endogenous stimuli, such as damage-associated molecular patterns and immune complexes, and involves activation in most cases of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, which produces reactive oxygen species (ROS). Recent study has reported that there are two different mechanisms of NETosis, including a lytic NETosis and a vital NETosis. Lytic NETosis begins with nuclear delobulation and the disassembly of the nuclear envelope and continues with loss of cellular polarization, chromatin decondensation and plasma membrane rupture. Vital NETosis can occur independently of cell death and involves the secreted expulsion of nuclear chromatin that is accompanied by the release of granule proteins through degranulation.
Class
Organismal Systems; Immune system
Pathway map
epz04613  Neutrophil extracellular trap formation
epz04613

Organism
Equus przewalskii (Przewalski's horse) [GN:epz]
Gene
103540860  FCGR3A; Fc fragment of IgG receptor IIIa [KO:K06463]
103565660  SYK; spleen associated tyrosine kinase [KO:K05855] [EC:2.7.10.2]
103548805  MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]
103554541  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
103549630  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
103543290  dual specificity mitogen-activated protein kinase kinase 2-like [KO:K04369] [EC:2.7.12.2]
103547261  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
103562408  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
103540976  cytochrome b-245 heavy chain [KO:K21421] [EC:1.-.-.-]
103556000  NCF1; neutrophil cytosolic factor 1 [KO:K08011]
103552012  NCF2; neutrophil cytosolic factor 2 [KO:K08010]
103559912  NCF4; neutrophil cytosolic factor 4 [KO:K08012]
103552260  ras-related C3 botulinum toxin substrate 1-like [KO:K04392]
103564464  RAC2; ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) [KO:K07860]
103542844  TLR7; toll like receptor 7 [KO:K05404]
103540598  TLR8; toll like receptor 8 [KO:K10170]
103544822  ELANE; elastase, neutrophil expressed [KO:K01327] [EC:3.4.21.37]
103546343  MPO; myeloperoxidase [KO:K10789] [EC:1.11.2.2]
103551082  ACTG1; actin gamma 1 [KO:K05692]
103547895  ACTB; actin beta [KO:K05692]
103566485  VDAC1; voltage dependent anion channel 1 [KO:K05862]
103560633  VDAC2; voltage dependent anion channel 2 [KO:K15040]
103540389  VDAC3; voltage dependent anion channel 3 [KO:K15041]
103549138  SLC25A4; solute carrier family 25 member 4 [KO:K05863]
103545106  ADP/ATP translocase 3-like [KO:K05863]
103562821  SLC25A31; solute carrier family 25 member 31 [KO:K05863]
103540840  ADP/ATP translocase 3-like [KO:K05863]
103548120  PPIF; peptidylprolyl isomerase F [KO:K09565] [EC:5.2.1.8]
103565774  PADI4; peptidyl arginine deiminase 4 [KO:K24669] [EC:3.5.3.15]
103562625  uncharacterized LOC103562625 [KO:K06856]
103562621  putative V-set and immunoglobulin domain-containing protein 7 [KO:K06856]
103540002  high affinity immunoglobulin gamma Fc receptor I-like [KO:K06498]
103540857  low affinity immunoglobulin gamma Fc region receptor II-a-like [KO:K06472]
103540858  FCGR2A; Fc fragment of IgG receptor IIa [KO:K06472]
103547251  ITGAM; integrin subunit alpha M [KO:K06461]
103543384  integrin beta-2-like [KO:K06464]
103547219  ITGAL; integrin subunit alpha L [KO:K05718]
103560605  CLEC7A; C-type lectin domain family 7 member A [KO:K10074]
103560907  SRC; SRC proto-oncogene, non-receptor tyrosine kinase [KO:K05704] [EC:2.7.10.2]
103562440  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
103559733  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]
103561633  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
103542193  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
103562208  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
103558212  PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11]
103558165  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
103556196  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
103540772  ATG7; autophagy related 7 [KO:K08337]
103554199  N-formyl peptide receptor 2-like [KO:K04173]
103554200  N-formyl peptide receptor 2-like [KO:K04173]
103554201  N-formyl peptide receptor 2-like [KO:K04173]
103549076  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
103554655  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform-like [KO:K00922] [EC:2.7.1.153]
103552150  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
103548220  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
103551868  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
103561550  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
103560497  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
103540249  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
103555421  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
103552237  MTOR; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
103556719  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
103543692  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
103540378  C3; complement C3 [KO:K03990]
103556844  CR1L; complement C3b/C4b receptor 1 like [KO:K04011]
103541409  complement receptor type 1-like [KO:K04011]
103556836  CR1; complement C3b/C4b receptor 1 (Knops blood group) [KO:K04011]
103550423  C5; complement C5 [KO:K03994]
103567448  C5AR1; complement C5a receptor 1 [KO:K04010]
103549273  HMGB1; high mobility group box 1 [KO:K10802]
103553736  TLR2; toll like receptor 2 [KO:K10159]
103562040  TLR4; toll like receptor 4 [KO:K10160]
103565534  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
103563198  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
103559485  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
103559491  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
103551206  ITGA2B; integrin subunit alpha 2b [KO:K06476]
103560746  ITGB3; integrin subunit beta 3 [KO:K06493]
103553817  FGA; fibrinogen alpha chain [KO:K03903]
103553816  FGB; fibrinogen beta chain [KO:K03904]
103553818  FGG; fibrinogen gamma chain [KO:K03905]
103560661  GP1BA; glycoprotein Ib platelet alpha subunit [KO:K06261]
103546989  VWF; von Willebrand factor [KO:K03900]
103554471  SELP; selectin P [KO:K06496]
103551439  SELPLG; selectin P ligand [KO:K06544]
103566647  AGER; advanced glycosylation end-product specific receptor [KO:K19722]
103559837  caspase-13-like [KO:K04394] [EC:3.4.22.57 3.4.22.64]
103559840  caspase-13-like [KO:K04394] [EC:3.4.22.57 3.4.22.64]
103559838  CASP1; caspase 1 [KO:K01370] [EC:3.4.22.36]
103561591  GSDMD; gasdermin D [KO:K20917]
103553126  HAT1; histone acetyltransferase 1 [KO:K11303] [EC:2.3.1.48]
103554951  histone H2A.V [KO:K11251]
103543405  core histone macro-H2A.1 [KO:K11251]
103549382  core histone macro-H2A.2 [KO:K11251]
103547604  histone H2A type 2-A [KO:K11251]
103547608  histone H2A type 2-C [KO:K11251]
103547610  histone H2A type 2-B [KO:K11251]
103565483  histone H2A.J [KO:K11251]
103564491  histone H2A-Bbd type 1-like [KO:K11251]
103560570  histone H2A.Z [KO:K11251]
103560824  histone H2A type 3 [KO:K11251]
103562039  histone H2A-Bbd type 1-like [KO:K11251]
103563929  histone H2A type 1-H-like [KO:K11251]
103563931  histone H2A type 1-like [KO:K11251]
103565197  histone H2A type 1-D [KO:K11251]
103565202  histone H2A type 1-E-like [KO:K11251]
103565205  histone H2A type 1 [KO:K11251]
103565440  histone H2A type 1-H [KO:K11251]
103565442  histone H2A type 1-like [KO:K11251]
103565454  histone H2A type 1-H-like [KO:K11251]
103565456  histone H2A type 1-like [KO:K11251]
103556151  histone H2A type 1-E [KO:K11251]
103556153  histone H2A type 1-like [KO:K11251]
103543494  histone H2A-Bbd type 2/3 [KO:K11251]
103543233  histone H2A-Bbd type 1-like [KO:K11251]
103547603  histone H2B type 2-E [KO:K11252]
103547607  histone H2B type 2-E [KO:K11252]
103541127  histone H2B type 1-like [KO:K11252]
103564180  late histone H2B.L4-like [KO:K11252]
103542737  late histone H2B.L4-like [KO:K11252]
103542738  late histone H2B.L4-like [KO:K11252]
103560825  histone H2B type 3-B [KO:K11252]
103560826  histone H2B type 3-A-like [KO:K11252]
103563925  histone H2B type 1-B-like [KO:K11252]
103565188  histone H2B type 1 [KO:K11252]
103565192  histone H2B type 1-M [KO:K11252]
103565194  histone H2B type 1 [KO:K11252]
103565198  histone H2B type 1-like [KO:K11252]
103565199  histone H2B type 1 [KO:K11252]
103565203  histone H2B type 2-E-like [KO:K11252]
103565206  histone H2B type 1-L [KO:K11252]
103565439  histone H2B type 1-B [KO:K11252]
103565443  histone H2B type 1-B [KO:K11252]
103565449  histone H2B type 2-E-like [KO:K11252]
103565458  histone H2B 1/2 [KO:K11252]
103539999  histone H2B type 2-F-like [KO:K11252]
103556152  histone H2B type 1-B [KO:K11252]
103556168  histone H2B type 1-A [KO:K11252]
103547605  histone H4 [KO:K11254]
103565482  histone H4 [KO:K11254]
103563926  histone H4 [KO:K11254]
103565186  histone H4 [KO:K11254]
103565193  histone H4 [KO:K11254]
103565204  histone H4 [KO:K11254]
103565207  histone H4 [KO:K11254]
103565444  histone H4 [KO:K11254]
103565445  histone H4 [KO:K11254]
103556157  histone H4 [KO:K11254]
103546590  H3F3B; H3 histone, family 3B [KO:K11253]
103547606  histone H3 [KO:K11253]
103568021  histone H3.3 [KO:K11253]
103560823  histone H3.1 [KO:K11253]
103565196  histone H3.1-like [KO:K11253]
103565208  histone H3.1-like [KO:K11253]
103565441  histone H3.1 [KO:K11253]
103565451  histone H3.1 [KO:K11253]
103562558  histone H3.3 [KO:K11253]
103540001  histone H3-like [KO:K11253]
103555951  histone H3.3-like [KO:K11253]
103556155  histone H3.1 [KO:K11253]
103556158  histone H3.1 [KO:K11253]
103552097  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
103561341  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
103550705  HDAC3; histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
103551196  HDAC5; histone deacetylase 5 [KO:K11406] [EC:3.5.1.98]
103555986  HDAC4; histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
103546792  HDAC7; histone deacetylase 7 [KO:K11408] [EC:3.5.1.98]
103563223  HDAC8; histone deacetylase 8 [KO:K11405] [EC:3.5.1.98]
103547671  HDAC9; histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
103559484  HDAC10; histone deacetylase 10 [KO:K18671] [EC:3.5.1.98]
103556786  HDAC11; histone deacetylase 11 [KO:K11418] [EC:3.5.1.98]
103561062  CTSG; cathepsin G [KO:K01319] [EC:3.4.21.20]
103556035  protegrin-2-like [KO:K13916]
103567911  cathelicidin-4-like [KO:K13916]
103544388  H(+)/Cl(-) exchange transporter 4 [KO:K05012]
103554068  CLCN3; chloride voltage-gated channel 3 [KO:K05012]
103541123  CLCN5; chloride voltage-gated channel 5 [KO:K05012]
103552037  AQP9; aquaporin 9 [KO:K09877]
Compound
C00027  Hydrogen peroxide
C00039  DNA
C00076  Calcium cation
C00165  Diacylglycerol
C00338  Lipopolysaccharide
C00464  Mannan
C00518  Hyaluronate
C00551  beta-D-Glucan
C00704  Superoxide
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05151  12-O-Tetradecanoylphorbol 13-acetate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C11221  Formylmethionyl-leucyl-phenylalanine methyl ester
Reference
PMID:29543328
  Authors
Van Avondt K, Hartl D
  Title
Mechanisms and disease relevance of neutrophil extracellular trap formation.
  Journal
Eur J Clin Invest 48 Suppl 2:e12919 (2018)
DOI:10.1111/eci.12919
Reference
PMID:31518165
  Authors
Sorvillo N, Cherpokova D, Martinod K, Wagner DD
  Title
Extracellular DNA NET-Works With Dire Consequences for Health.
  Journal
Circ Res 125:470-488 (2019)
DOI:10.1161/CIRCRESAHA.119.314581
Reference
PMID:28990587
  Authors
Papayannopoulos V
  Title
Neutrophil extracellular traps in immunity and disease.
  Journal
Nat Rev Immunol 18:134-147 (2018)
DOI:10.1038/nri.2017.105
Reference
PMID:24837201
  Authors
Liu FC, Chuang YH, Tsai YF, Yu HP
  Title
Role of neutrophil extracellular traps following injury.
  Journal
Shock 41:491-8 (2014)
DOI:10.1097/SHK.0000000000000146
Reference
PMID:27570525
  Authors
Yang H, Biermann MH, Brauner JM, Liu Y, Zhao Y, Herrmann M
  Title
New Insights into Neutrophil Extracellular Traps: Mechanisms of Formation and Role in Inflammation.
  Journal
Front Immunol 7:302 (2016)
DOI:10.3389/fimmu.2016.00302
Reference
PMID:28983472
  Authors
Zawrotniak M, Bochenska O, Karkowska-Kuleta J, Seweryn-Ozog K, Aoki W, Ueda M, Kozik A, Rapala-Kozik M
  Title
Aspartic Proteases and Major Cell Wall Components in Candida albicans Trigger the Release of Neutrophil Extracellular Traps.
  Journal
Front Cell Infect Microbiol 7:414 (2017)
DOI:10.3389/fcimb.2017.00414
Reference
PMID:29382950
  Authors
Honda M, Kubes P
  Title
Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system.
  Journal
Nat Rev Gastroenterol Hepatol 15:206-221 (2018)
DOI:10.1038/nrgastro.2017.183
Reference
PMID:31416265
  Authors
Hamam HJ, Palaniyar N
  Title
Post-Translational Modifications in NETosis and NETs-Mediated Diseases.
  Journal
Biomolecules 9:E369 (2019)
DOI:10.3390/biom9080369
Reference
PMID:31767647
  Authors
Burgener SS, Schroder K
  Title
Neutrophil Extracellular Traps in Host Defense.
  Journal
Cold Spring Harb Perspect Biol 12:a037028 (2020)
DOI:10.1101/cshperspect.a037028
Reference
PMID:33202203
  Authors
Vorobjeva NV, Chernyak BV
  Title
NETosis: Molecular Mechanisms, Role in Physiology and Pathology.
  Journal
Biochemistry (Mosc) 85:1178-1190 (2020)
DOI:10.1134/S0006297920100065
Reference
PMID:31416173
  Authors
Ravindran M, Khan MA, Palaniyar N
  Title
Neutrophil Extracellular Trap Formation: Physiology, Pathology, and Pharmacology.
  Journal
Biomolecules 9:E365 (2019)
DOI:10.3390/biom9080365
Reference
PMID:28267716
  Authors
Jorch SK, Kubes P
  Title
An emerging role for neutrophil extracellular traps in noninfectious disease.
  Journal
Nat Med 23:279-287 (2017)
DOI:10.1038/nm.4294
Reference
PMID:31342866
  Authors
Goggs R, Jeffery U, LeVine DN, Li RHL
  Title
Neutrophil-Extracellular Traps, Cell-Free DNA, and Immunothrombosis in Companion Animals: A Review.
  Journal
Vet Pathol 57:6-23 (2020)
DOI:10.1177/0300985819861721
Reference
PMID:27876233
  Authors
Kim SJ, Jenne CN
  Title
Role of platelets in neutrophil extracellular trap (NET) production and tissue injury.
  Journal
Semin Immunol 28:546-554 (2016)
DOI:10.1016/j.smim.2016.10.013
Reference
PMID:29572545
  Authors
de Bont CM, Boelens WC, Pruijn GJM
  Title
NETosis, complement, and coagulation: a triangular relationship.
  Journal
Cell Mol Immunol 16:19-27 (2019)
DOI:10.1038/s41423-018-0024-0
Reference
PMID:31129510
  Authors
Zawrotniak M, Bartnicka D, Rapala-Kozik M
  Title
UVA and UVB radiation induce the formation of neutrophil extracellular traps by human polymorphonuclear cells.
  Journal
J Photochem Photobiol B 196:111511 (2019)
DOI:10.1016/j.jphotobiol.2019.111511
Reference
PMID:21293492
  Authors
Remijsen Q, Kuijpers TW, Wirawan E, Lippens S, Vandenabeele P, Vanden Berghe T
  Title
Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality.
  Journal
Cell Death Differ 18:581-8 (2011)
DOI:10.1038/cdd.2011.1
Reference
PMID:23819131
  Authors
Zawrotniak M, Rapala-Kozik M
  Title
Neutrophil extracellular traps (NETs) - formation and implications.
  Journal
Acta Biochim Pol 60:277-84 (2013)
Reference
PMID:28373871
  Authors
Rosales C
  Title
Fcgamma Receptor Heterogeneity in Leukocyte Functional Responses.
  Journal
Front Immunol 8:280 (2017)
DOI:10.3389/fimmu.2017.00280
Reference
PMID:25716722
  Authors
Vorobjeva NV, Pinegin BV
  Title
Neutrophil extracellular traps: mechanisms of formation and role in health and disease.
  Journal
Biochemistry (Mosc) 79:1286-96 (2014)
DOI:10.1134/S0006297914120025
Reference
PMID:28220120
  Authors
Delgado-Rizo V, Martinez-Guzman MA, Iniguez-Gutierrez L, Garcia-Orozco A, Alvarado-Navarro A, Fafutis-Morris M
  Title
Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview.
  Journal
Front Immunol 8:81 (2017)
DOI:10.3389/fimmu.2017.00081
Reference
PMID:30023352
  Authors
Fonseca Z, Diaz-Godinez C, Mora N, Aleman OR, Uribe-Querol E, Carrero JC, Rosales C
  Title
Entamoeba histolytica Induce Signaling via Raf/MEK/ERK for Neutrophil Extracellular Trap (NET) Formation.
  Journal
Front Cell Infect Microbiol 8:226 (2018)
DOI:10.3389/fcimb.2018.00226
Reference
PMID:27923601
  Authors
Agraz-Cibrian JM, Giraldo DM, Mary FM, Urcuqui-Inchima S
  Title
Understanding the molecular mechanisms of NETs and their role in antiviral innate immunity.
  Journal
Virus Res 228:124-133 (2017)
DOI:10.1016/j.virusres.2016.11.033
Reference
PMID:27698656
  Authors
Schonrich G, Raftery MJ
  Title
Neutrophil Extracellular Traps Go Viral.
  Journal
Front Immunol 7:366 (2016)
DOI:10.3389/fimmu.2016.00366
Reference
PMID:22817992
  Authors
Saitoh T, Komano J, Saitoh Y, Misawa T, Takahama M, Kozaki T, Uehata T, Iwasaki H, Omori H, Yamaoka S, Yamamoto N, Akira S
  Title
Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1.
  Journal
Cell Host Microbe 12:109-16 (2012)
DOI:10.1016/j.chom.2012.05.015
Reference
PMID:29908538
  Authors
Kumar S, Gupta E, Kaushik S, Jyoti A
  Title
Neutrophil Extracellular Traps: Formation and Involvement in Disease Progression.
  Journal
Iran J Allergy Asthma Immunol 17:208-220 (2018)
Related
pathway
epz04010  MAPK signaling pathway
epz04020  Calcium signaling pathway
epz04140  Autophagy - animal
epz04151  PI3K-Akt signaling pathway
epz04610  Complement and coagulation cascades
epz04611  Platelet activation
epz04620  Toll-like receptor signaling pathway
epz04621  NOD-like receptor signaling pathway
epz04666  Fc gamma R-mediated phagocytosis
KO pathway
ko04613   
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