polymorphonuclear leukocytes ( pmns ) , or neutrophils , are most abundant population of white blood cells , comprising 50 - 75% of leukocytes in peripheral blood . these cells employ several strategies to fight infections , two of which have been well established and described : phagocytosis and degranulation , which releases lytic enzymes . they are also characterized by their ability to form reactive oxygen species ( ros ) by nadph oxidase which have antimicrobial potential . in 2004 a novel mechanism that combats infections was described . neutrophils can form extracellular web - like structures , called neutrophil extracellular traps ( nets ) , made up of decondensed chromatin associated with antimicrobial proteins and peptides . since this discovery a lot of studies have been performed to evaluate the formation process and physiological role of nets in defense against invading pathogens . this unique structure is considered to play a role not only in host defense mechanisms , but also to have unfavorable consequences when the balance between nets formation and clearance is disturbed . thus , a significant field of net research is centered on the relationship between nets and inflammation , infection or autoimmune diseases . in this review , we will present current knowledge about this sophisticated relationship and the role of nets in infections as well as in certain diseases . upon activation , the chromatin in neutrophils starts to decondensate and forms complexes with over 30 granular and cytoplasmic proteins , which are finally extruded into the extracellular space . polymorphonuclear leukocytes not only act defensively in the bloodstream but also may cover large areas within the solid tissues when crawling . interestingly , at most 20 - 25% of these residual cells release nets to fight threats [ 2 , 4 ] . neutrophil extracellular traps were primarily observed as fragile fibers composed of smooth stretches with globular domains , which aggregated into larger strands . further examinations showed that nets structures may be degraded by treatment with dnases and not by proteases , therefore nuclear dna ( chromatin ) is certain to be the backbone of nets structure [ 2 , 5 ] . this bioframe is ornamented with a number of protein components which stabilize this structure as well show microbicidal properties ( table 1 ) . main neutrophil derived proteins which ornaments neutrophils extracellular trap structure the role of extracellular traps is to create a specific space with high local concentration of antimicrobial agents , preferably at the site of infection . pathogens , their products , as well as variety of biochemical agents , i.e. phorbol-12-myristate-13-acetate ( pma ) , lipopolysaccharide ( lps ) , interleukin-8 ( il-8 ) , tumor necrosis factor  ( tnf- ) , monosodium urate crystals , nitric oxide ( no ) , autoantibodies and immune complexes can initiate traps formation . moreover , interaction between neutrophils and platelets via toll - like - receptor 4 ( tlr4 ) leads to the formation of nets in septic blood [ 3 , 7 ] . recent studies have shown that macrophages are responsible for nets clearing after they execute their function . this path starts when dnase i breaks extracellular traps structure and the complement factor c1q opsonizes the debris . subsequently nets are internalized by macrophages due to cytochalasin d - dependent endocytic process . actively engulfed nets are apparently degraded in lysosomes , but it is possible that other intracellular compartments are also involved . several studies have shown that mast cells and macrophages are also prone to create similar structures in response to pathogens and certain stimulatory agents . interestingly , extracellular traps released by eosinophils are made of mitochondrial dna , therefore they lack histones , furthermore this process never causes cell death . to date , two mechanisms of nets formation are known . the major route , a slow lytic cell death mechanism , is also known as suicidal netosis . the second strategy , called vital netosis , enables cells to continue their functions , such as crawling and phagocytosis after net release . netosis via cell death occurs 2 - 4 hours after stimulation , whereas vital netosis occurs rapidly , approximately 5 - 60 minutes after stimulation . toll - like receptor 2 ( tlr2 ) and complement factor 3 contribute to both suicidal and vital netosis , but are not sufficient to stimulate nets formation in isolated pmns [ 3 , 4 ] . when pmn undergoes suicidal netosis , its nuclear and granule membranes disassemble and decondensation of chromatin occurs . this process is continued in the cytosol , where granular and cytoplasmic proteins associate with dna and histones . this hypothesis was supported by following findings : pmns of nox2-deficient ( nox2 is a subunit of nadph ) mice could not form nets after the stimulation with pma , just as neutrophils from patients suffering from chronic granulomatous disease where nox2 is defective or absent [ 1 , 10 , 11 ] . reactive oxygen species participate in nets formation , but the exact molecular mechanism is yet poorly understood . according to reported data , ros induce the translocation of neutrophil elastase from the primary granules to the nucleus , where it degrades histones and causes chromatin decondensation . nevertheless , it has been described that it is possible to release nets via cell death mechanism independently from ros . polymorphonuclear leukocytes stimulation with staphylococcus aureus culture may release nets before any ros can be detected . thus , the ros participate only in the production of certain type of extracellular traps [ 12 , 13 ] . there are five known isoforms of peptidylarginine deiminase ( pad ) , of which only pad4 can be translocated to the nucleus and catalyse deamination of arginine to citrulline . however , pma as a strong inducer of netosis , is simultaneously an activator of protein kinase c ( pkc ) , an inhibitor of pad4 . these observations indicate that there is no absolute connection between nets formation and citrullination of histones and other regulating mechanisms are also involved [ 14 , 15 ] . the addition of wortmannin , pharmacological inhibitor of autophagy , impairs chromatin decondensation , but does not affect nadph oxidase - dependent oxidative burst . it is worth noting , that suicidal netosis is different from necrosis and apoptosis . during netosis there is no dna fragmentation and caspases appear not to be involved , what distinguish this process from apoptosis additionally in early necrosis there are no morphological changes in the nucleus , whereas nets release is preceded by nuclear membranes disintegration and formation of vesicles . the process starts from the separation of the nuclear membranes , followed by decondensation of chromatin in the intermembrane space . vesicles containing chromatin and antimicrobial proteins are formed and they accumulate near to the plasma membrane . finally vesicles release their content into the extracellular space , where proteins and chromatin assemble into nets . it has been documented that there is another process enabling nets formation  the release of mitochondrial dna . anuclear pmns , cytoplasts or motile cytokineplasts , maintain the ability to chemotax and engulf bacteria in the bloodstream . the fact that pmns can function without nucleus is not unlikely as it has been reported that neutrophils may express the same protein ( survivine ) as erythrocytes , another anucleated cells . mature pmns are able to synthesize this protein after stimulation with macrophage - colony- stimulating factor [ 1619 ] . neutrophil extracellular traps are being formed to trap and kill a variety of pathogens including bacteria , fungi , viruses and parasites . considering available scientific data , it seems that nets formation occurs in response to specific microbes , but properties of pathogens that are necessary to induce netosis remain to be further investigated . neutrophil extracellular traps play a vital role in the defense against wide range of bacteria . it was proven that netosis occurs after stimulation with pathogens such as streptococcus pneumoniae , streptococcus pyogenes , staphylococcus aureus , escherichia coli , salmonella typhimurium or shigella flexnerii . besides trapping and killing bacteria , active components of extracellular traps can neutralize virulence factors . as an example invasion plasmid antigens : ipab and icsa ( used for cell - to - cell spread ) from s. flexnerii , are degraded by neutrophil elastase ( ne ) which is essential part of nets [ 2 , 20 , 21 ] . moreover , it has been indicated that some strains of mycobacterium tuberculosis and mycobacterium canettii , might trigger net formation . there are some strategies developed by bacteria to escape from extracellular traps killing mechanism . as an example s. pneumoniae has polysaccharide capsule that reduces net binding . subsequently the surface charge of cell turns from negative into positive , disrupting its affinity to antibacterial factors . s. pyogenes produces dnase sda1 and virulence factor m1 neutralizing cathelicidin , the antimicrobial component of net [ 22 , 24 ] . it has been reported that nets may help to avoid spreading of bacterial biofilm coating the dental root in patients with periodontitis . on the one hand , the bacterial proliferation is prevented by overproduction of the gingival cervical fluid , around the tooth necks , containing neutrophils producing extracellular traps . showed that biofilm in periodontitis is prone to efficient production of dnases which break the trap 's bioframe . in normal conditions the balance between biofilm degradation and bacterial protection is established . urban et al . showed that the antimicrobial heterodimer calprotectin is the major antifungal component of extracellular traps . these authors showed that calprotectin deficient mice are highly prone to candidiasis and aspergillosis thus , they postulated that this protein appears to be one of main factors involved in fungal clearance [ 26 , 27 ] . it is unresolved why extracellular trap are more beneficial during fungal infection than phagocytosis or degranulation . it was shown that invasive forms of c. albicans are being effectively killed within trap structures rather than with use of any other neutrophil 's weapons . this was strictly connected with the fact that hyphae are too big for effective phagocytosis . bruns et al . showed that aspergillus fumigatus hyphae are stronger inducers of nets than conidia . this alteration of host - pathogen interaction dynamics is explained by presence of hydrophobin roda . this protein is expressed only upon the surface of conidia and makes conidia immunologically inert , thus leading to reduced net formation . they showed that neutrophils detect hiv-1 via two toll - like receptors ( tlrs ) : tlr7 and tlr8 , which recognize viral nucleic acids . engagement of tlr7 and tlr8 induces the intracellular cascade of events which in the end promote generation of reactive oxygen species that trigger net formation , leading to net - dependent hiv-1 elimination . hiv-1 counteracts this defensive response by inducing c - type lectin cd209-dependent production of interleukin ( il)-10 by dendritic cells in order to inhibit net formation . overproduction of il-10 suppresses the reactive oxygen species - dependent generation of nets induced upon tlr7 and tlr8 engagement , resulting in disrupted net - dependent hiv-1 elimination [ 29 , 30 ] . another virus that have been described to initiate netosis is influenza virus which causes acute respiratory distress syndrome ( ards ) . administration of anti - myeloperoxidase antibody and an inhibitor of superoxide dismutase prevent traps from being formed . this observation indicates that nets generation is induced by redox enzymes during influenza infection and superoxide and h2o2 produced by epithelium are mediators in this process . some scientists showed that net forms a space that physically contain the pathogen but does not kill it . neutrophil extracellular traps have been also found in peripheral blood of patiens infected with plasmodium falciparum . besides these benefits , there are a number of studies pointing that netosis is a double - edge sword of the immunity . despite the beneficial role of preventing infectious threats nets formation participates in the pathogenesis of many diseases , including inflammatory and autoimmune conditions . it is believed that netosis has unfavorable consequences when happens in the inappropriate localization , with the inadequate intensity or in the wrong time . to date , netosis is considered as a process causing lung epithelium cells damage in patients with cystic fibrosis ( cf ) . cystic fibrosis patients suffer from chronic lung infection and inflammation due to the secretion of viscous sputum . , the extracellular dna found in cf sputum was thought to originate from dying necrotic or apoptotic neutrophils and epithelial cells . however , some studies showed that in that case , the chromatin would remain condensed and would not be found in complex with neutrophil granular proteins . thus , it was proposed that genomic dna ornamented by neutrophil elastase ( ne ) and mpo , have the most detrimental effect on lung tissue . the elevated level of extracellular dna seems to be caused by the placentae derived factors , i.e. il-8 and placental micro - debris . there is a straight connection between nets generation and disease pathogenesis because preeclampsia episodes coexist with an increased levels of cell - free dna in plasma . histones bind to endothelium surface where they promote platelets aggregation and platelet - dependent thrombin generation . simultaneously , due to the presence of extracellular chromatin fibers , scaffolds in circulation are being formed . these findings suggest , that netosis may sharply increase the risk of deep vein thrombosis . contradicting results have been observed when studying the role of netosis in cancer and this area needs to be further investigated . some studies show that cancer patients who suffer from severe postoperative infections are more likely to die from metastasis than those who do not . it was proposed that nets may trap circulating tumor cells and enhance their adhesion to distant organ sites , thus promote metastasis . nonetheless , neutrophil elastase , one of the main components of traps , seems to have ability to enhance tumor - cell proliferation . nets formation is involved at least in pathogenesis of anca vasculitis , systemic lupus erythematosus ( sle ) and rheumatoid arthritis [ 3 , 40 , 41 ] . neutrophil extracellular trap itself is an autological structure and it persistent existence can cause overproduction of autoantibodies against dna , rna and specific proteins . there are at least two pathways by which net proteins could have impact on sle pathogenesis . neutrophil extracellular trap may contribute to organs damage , due to the potential toxicity of net 's ornaments . in a result they have been detected at increased levels in sle patients compared with healthy ones . the second concept is that net proteins may be specifically modified and positioned to break tolerance and thereby trigger or exacerbate autoimmunity . idea that modified proteins serve as autoantigens in sle is known for some time but attempts to link them to extracellular traps are new . studies showed that net - proteins like c1q , ne , histones , hmgb1 ( high - mobility group protein b1 ) , hnp ( human neutrophil peptide 1 ) , il-17 , ll37 , cathelicidin and mpo contribute to sle pathogenesis . the double edged sword of the immunity , as extracellular traps are called , can be both beneficial and threatful . neutrophils for many years were considered to be guardians fighting with prokaryotic and eukaryotic invaders . there is increasing evidence that nets play an important role in several infectious as well as noninfectious diseases . since the discovery of netosis neutrophils started to be considered as play prominent players in autoimmunity , inflammatory states and thrombosis .
neutrophil extracellular traps ( nets ) are developed by nature to protect the body from furious invaders . 
 on the other hand net s can play an important role in human pathology . 
 recent studies have shown that neutrophils are able to perform beneficial suicide to create an unique microbicidal net composed from cellular content attached to chromatic frame . 
 it is a powerful tool that primary serve as protector from severe infections , but this weapon is also a double ended sword of the immunity . if overproduced net s provoke certain autoimmune diseases , coagulation disorders and even cancer metastases . 
 moreover , due to the competition between host and pathogens , the microorganism have developed a width repertoire of sophisticated evading mechanisms , like creation of polysaccharide capsule or changes in cell wall charge . 
 therefore it is important to increase the knowledge about paths underlying net s formation and degradation processes if we want to efficiently fight with bacterial infections and certain diseases .