KEGG   PATHWAY: lav04613
Entry
lav04613                    Pathway                                
Name
Neutrophil extracellular trap formation - Loxodonta africana (African savanna elephant)
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
lav04613  Neutrophil extracellular trap formation
lav04613

Organism
Loxodonta africana (African savanna elephant) [GN:lav]
Gene
100653643  CAMP; cathelicidin antimicrobial peptide [KO:K13916]
100653731  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100653969  [KO:K11251]
100654055  [KO:K11253]
100654406  FCGR1B; high affinity immunoglobulin gamma Fc receptor IB isoform X1 [KO:K06498]
100654429  ITGA2B; LOW QUALITY PROTEIN: integrin alpha-IIb [KO:K06476]
100654442  TLR2; toll-like receptor 2 [KO:K10159]
100654493  TLR4; toll-like receptor 4 [KO:K10160]
100654618  ACTB; actin, cytoplasmic 1 [KO:K05692]
100654642  [KO:K01319] [EC:3.4.21.20]
100654730  RELA; transcription factor p65 isoform X2 [KO:K04735]
100654974  FCGR1A; high affinity immunoglobulin gamma Fc receptor I [KO:K06498]
100654976  ATG7; ubiquitin-like modifier-activating enzyme ATG7 isoform X1 [KO:K08337]
100655117  [KO:K11251]
100655240  [KO:K11253]
100655324  SLC25A6; ADP/ATP translocase 3 [KO:K05863]
100655399  [KO:K11253]
100655685  [KO:K11251]
100655727  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100655878  [KO:K21421] [EC:1.-.-.-]
100656084  HDAC7; histone deacetylase 7 isoform X2 [KO:K11408] [EC:3.5.1.98]
100656308  VDAC3; voltage-dependent anion-selective channel protein 3 [KO:K15041]
100656378  HAT1; histone acetyltransferase type B catalytic subunit [KO:K11303] [EC:2.3.1.48]
100656492  [KO:K11251]
100656778  [KO:K11251]
100656926  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100657060  [KO:K11252]
100657350  [KO:K11253]
100657464  GP1BA; platelet glycoprotein Ib alpha chain [KO:K06261]
100657489  C3; complement C3 [KO:K03990]
100657536  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100657549  [KO:K11406] [EC:3.5.1.98]
100657587  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100657634  [KO:K11251]
100657920  [KO:K11252]
100657948  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100658203  [KO:K11251]
100658236  AQP9; aquaporin-9 isoform X1 [KO:K09877]
100658239  ITGAL; integrin alpha-L [KO:K05718]
100658240  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100658340  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100658484  [KO:K11253]
100658765  [KO:K11252]
100658990  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
100659422  CLEC7A; C-type lectin domain family 7 member A isoform X1 [KO:K10074]
100659586  [KO:K11251]
100659892  HDAC10; LOW QUALITY PROTEIN: histone deacetylase 10 [KO:K18671] [EC:3.5.1.98]
100659941  [KO:K11251]
100659990  [KO:K11251]
100660112  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100660148  [KO:K11252]
100660187  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100660405  ITGB3; integrin beta-3 isoform X1 [KO:K06493]
100660481  [KO:K11251]
100660750  C5AR1; C5a anaphylatoxin chemotactic receptor 1 [KO:K04010]
100661012  [KO:K11252]
100661039  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
100661062  NCF2; neutrophil cytosol factor 2 isoform X2 [KO:K08010]
100661296  [KO:K11251]
100661341  [KO:K04011]
100661497  AGER; advanced glycosylation end product-specific receptor isoform X2 [KO:K19722]
100661933  [KO:K04394] [EC:3.4.22.57 3.4.22.64]
100662013  MPO; myeloperoxidase [KO:K10789] [EC:1.11.2.2]
100662145  [KO:K11252]
100662194  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100662231  [KO:K06461]
100662291  HDAC8; histone deacetylase 8 isoform X3 [KO:K11405] [EC:3.5.1.98]
100662346  HDAC3; LOW QUALITY PROTEIN: histone deacetylase 3 [KO:K11404] [EC:3.5.1.98]
100662424  [KO:K11251]
100662489  SLC25A4; LOW QUALITY PROTEIN: ADP/ATP translocase 1 [KO:K05863]
100662792  [KO:K06461]
100662984  [KO:K11251]
100663098  VDAC1; voltage-dependent anion-selective channel protein 1 [KO:K05862]
100663116  HDAC9; LOW QUALITY PROTEIN: histone deacetylase 9 [KO:K11409] [EC:3.5.1.98]
100663184  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100663269  [KO:K11252]
100663551  [KO:K11253]
100663651  SYK; LOW QUALITY PROTEIN: tyrosine-protein kinase SYK [KO:K05855] [EC:2.7.10.2]
100663722  [KO:K11252]
100663829  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
100664204  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
100664283  [KO:K11253]
100664570  [KO:K11252]
100664844  SLC25A5; ADP/ATP translocase 2 [KO:K05863]
100665018  [KO:K11252]
100665045  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100665157  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100665256  ITGB2; integrin beta-2 isoform X1 [KO:K06464]
100665424  [KO:K11254]
100665537  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
100666003  CLCN5; H(+)/Cl(-) exchange transporter 5 isoform X1 [KO:K05012]
100666266  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100666280  [KO:K11254]
100666560  TLR8; toll-like receptor 8 isoform X2 [KO:K10170]
100666562  [KO:K11253]
100666572  [KO:K08009]
100666599  [KO:K11251]
100666845  HDAC1; histone deacetylase 1 isoform X2 [KO:K06067] [EC:3.5.1.98]
100666850  [KO:K11251]
100667137  [KO:K11252]
100667170  MAP3K7; mitogen-activated protein kinase kinase kinase 7 isoform X2 [KO:K04427] [EC:2.7.11.25]
100667419  [KO:K11252]
100667623  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100667708  [KO:K11251]
100667776  VDAC2; voltage-dependent anion-selective channel protein 2 [KO:K15040]
100668044  FPR1; fMet-Leu-Phe receptor [KO:K04172]
100668472  CLCN4; H(+)/Cl(-) exchange transporter 4 [KO:K05012]
100668564  [KO:K11253]
100668575  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
100668630  PPIF; peptidyl-prolyl cis-trans isomerase F, mitochondrial [KO:K09565] [EC:5.2.1.8]
100668844  [KO:K11252]
100668932  TLR7; toll-like receptor 7 isoform X2 [KO:K05404]
100669124  [KO:K11252]
100669563  SLC25A31; LOW QUALITY PROTEIN: ADP/ATP translocase 4 [KO:K05863]
100669688  [KO:K11251]
100669940  [KO:K11251]
100669973  [KO:K11252]
100670080  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
100670379  [KO:K11251]
100670474  [KO:K11251]
100670545  [KO:K11254]
100670564  NCF4; LOW QUALITY PROTEIN: neutrophil cytosol factor 4 [KO:K08012]
100670617  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858] [EC:3.1.4.11]
100670660  [KO:K11252]
100670743  ACTG1; actin, cytoplasmic 2 [KO:K05692]
100670942  [KO:K11252]
100671112  [KO:K11253]
100671226  [KO:K11251]
100671396  [KO:K11251]
100671429  AZU1; azurocidin [KO:K24665]
100671512  [KO:K11253]
100671560  VWF; von Willebrand factor [KO:K03900]
100671682  [KO:K11252]
100671733  PRKCG; LOW QUALITY PROTEIN: protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100671878  FGG; fibrinogen gamma chain [KO:K03905]
100672001  ELANE; neutrophil elastase [KO:K01327] [EC:3.4.21.37]
100672078  PRKCB; LOW QUALITY PROTEIN: protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
100672174  FGA; LOW QUALITY PROTEIN: fibrinogen alpha chain [KO:K03903]
100672435  PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
100672464  FGB; fibrinogen beta chain [KO:K03904]
100672618  [KO:K11253]
100672832  [KO:K11254]
100672861  [KO:K11251]
100673143  [KO:K11252]
100673297  HMGB1; high mobility group protein B1 [KO:K10802]
100673308  NCF1; LOW QUALITY PROTEIN: neutrophil cytosol factor 1 [KO:K08011]
100673331  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100673434  [KO:K11254]
100673540  HDAC2; LOW QUALITY PROTEIN: histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
100673728  [KO:K11251]
100674008  [KO:K11252]
100674832  [KO:K11251]
100675119  [KO:K11252]
100675184  HDAC11; histone deacetylase 11 isoform X1 [KO:K11418] [EC:3.5.1.98]
100675209  SELP; LOW QUALITY PROTEIN: P-selectin [KO:K06496]
100675393  [KO:K11252]
100675398  [KO:K11252]
100675475  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
100675496  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100675676  [KO:K11252]
100675681  [KO:K11251]
100675769  PADI4; protein-arginine deiminase type-4 [KO:K24669]
100676072  HDAC4; histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
100676110  [KO:K11254]
100676190  GSDMD; gasdermin-D isoform X2 [KO:K20917]
100676393  [KO:K11251]
100676780  C5; LOW QUALITY PROTEIN: complement C5 [KO:K03994]
100677090  CLCN3; H(+)/Cl(-) exchange transporter 3 isoform X5 [KO:K05012]
100677211  HDAC6; histone deacetylase 6 isoform X1 [KO:K11407] [EC:3.5.1.98]
100677739  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
104845913  [KO:K13916]
104846329  FCGR2A; low affinity immunoglobulin gamma Fc region receptor II-a isoform X2 [KO:K06472]
104846346  [KO:K06463]
104846796  SELPLG; P-selectin glycoprotein ligand 1 [KO:K06544]
104847364  [KO:K06856]
111748619  [KO:K11251]
111750617  [KO:K11252]
111752372  [KO:K11253]
111752373  [KO:K11253]
111752374  [KO:K11251]
111752375  [KO:K11254]
111752376  [KO:K11254]
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 9:369 (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 9:365 (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
lav04010  MAPK signaling pathway
lav04020  Calcium signaling pathway
lav04140  Autophagy - animal
lav04151  PI3K-Akt signaling pathway
lav04610  Complement and coagulation cascades
lav04611  Platelet activation
lav04620  Toll-like receptor signaling pathway
lav04621  NOD-like receptor signaling pathway
lav04666  Fc gamma R-mediated phagocytosis
KO pathway
ko04613   

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