Association of polymorphisms in the TNFA, TNFRSF1A and TNFRSF1B genes with lepromatous leprosy in Western Mexican patients.

INTRODUCTION: Studies in different populations have shown that single-nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha (TNFα) and TNF receptors 1 and 2 (TNFR1 and TNFR2) may be involved in the pathogenesis of lepromatous leprosy (LL). To further explore the results in a Mexican population, we compared the frequencies of the polymorphisms in - 308 G>A TNFA (rs1800629), - 383 A>C TNFRS1A (rs2234649), and + 196 T >G TNFSR1B (rs1061622) genes in LL patients (n = 133) and healthy subjects (n = 198). METHODOLOGY: The genotyping was performed with the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) technique. Statistical analysis was performed using the χ2 test, within the 95% confidence interval. Odds ratios (OR) were calculated and Hardy-Weinberg equilibrium was verified for all control subjects and patients. RESULTS: We found an association between the TNFSR1 -383 A>C genotype and the risk of lepromatous leprosy when leprosy patients were compared to controls (OR = 1.71, CI: 1.08-2.69, p = 0.02). Furthermore, it was also associated with the risk of LL in a dominant model (AC + CC vs AA, OR: 1.65, 95% CI: 1.05-2.057, p = 0.02). Similar genotype and allele frequencies for the SNPs TNFA - 308 G>A and TNFSR2 + 196 T>G were observed between leprosy patients and healthy subjects. CONCLUSIONS: The TNFSR1 -383 A>C could be a potential marker for the identification of high-risk populations. However, additional studies, using larger samples of different ethnic populations, are required.

Recombinant p40 Protein Promotes Expression of Occludin in HaCaT Keratinocytes: A Brief Communication.

The ability of epithelial barriers to perform as the first defense line against external damage derives from tight junctions, protein complexes that block microorganisms through the paracellular space. Indeed, disturbances of barrier permeability caused by bacterial metabolites and other inflammatory stimuli are the consequence of changes in protein expression in these complexes. Postbiotics, molecules derived from bacteria with beneficial effects on the host, improve barrier function through the activation of survival pathways in epithelial cells. Lacticaseibacillus rhamnosus GG secretes the muramidase p40, which protects intestinal barriers through an EGFR-dependent pathway. In this work, we cloned, expressed, and purified the recombinant p40 protein from L. rhamnosus GR-1 to evaluate its effect on cell viability, cell cytotoxicity, TEER, and protein levels of tight junctions, as well as EGFR activation via Western blot on HaCaT keratinocytes subjected to LPS. We found a novel mutation at residue 368 that does not change the structure of p40. Our protein also reduces the LPS-induced increase in cell cytotoxicity when it is added prior to this stimulus. Furthermore, although LPS did not cause changes in barrier function, p40 increased TEER and occludin expression in HaCaT, but unlike previous work with p40 from LGG, we found that recombinant p40 did not activate EGFR. This suggests that recombinant p40 enhances epithelial barrier function through distinct signaling pathways.

Effect of Antioxidant Supplementation on NET Formation Induced by LPS In Vitro; the Roles of Vitamins E and C, Glutathione, and N-acetyl Cysteine.

Neutrophil extracellular traps (NETs) require reactive oxygen species (ROS) to eliminate pathogens by inducing oxidative stress. However, this process can also cause tissue damage to the host. Neutrophils contain high concentrations of vitamin C (1.5 mM) compared to the bloodstream (0.1 mM), and this antioxidant can interact with vitamin E and glutathione (GSH) inside the cell to maintain the redox balance. Previous studies have investigated the effect of vitamins E or C and N-acetyl cysteine (NAC) on NET formation, but the interactions of these molecules in neutrophils remain unknown. In this study, we investigated the effect of antioxidants alone and two combinations on NET formation and oxidative stress. Neutrophils were pre-loaded with GSH + NAC or vitamin E + vitamin C + GSH + NAC (termed ALL), and LPS-induced NET formation was assessed using fluorometry and immunofluorescence. Antioxidant effects were evaluated by measuring the total antioxidant capacity (TAC), GSH/GSSG ratio, ROS production, nitrite + nitrate levels, and lipid peroxidation. Our results showed that even low doses of antioxidants are capable of decreasing NETs. Furthermore, the combinations augmented TAC and GSH/GSSG ratio and decreased ROS, nitrites + nitrates, and malondialdehyde (MDA) levels in supplemented neutrophils in vitro.

Non-fitness status of peripheral NK cells defined by decreased NKp30 and perforin, and increased soluble B7H6, in cervical cancer patients.

The NKp30 receptor is one of the three natural cytotoxic receptors reported in NK cells. This receptor is codified by the NCR3 gene, which encodes three isoforms, a consequence of the alternative splicing of exon 4. A greater expression of the three isoforms (A, B, and C), along with low levels of the NKp30 ligand B7H6, has been reported as a positive prognostic factor in different cancer types. Here, in patients with cervical cancer and precursor lesions, we report an altered immune-phenotype, characterized by non-fitness markers, that correlated with increased disease stage, from CIN 1 to FIGO IV. While overall NK cell numbers increased, loss of NKp30+ NK cells, especially in the CD56dim subpopulation, was found. Perforin levels were decreased in these cells. Decreased expression of the NKp30 C isoform and overexpression of soluble B7H6 was found in cervical cancer patients when compared against healthy subjects. PBMCs from healthy subjects downregulated NKp30 isoforms after co-culture with B7H6-expressing tumour cells. Taken together, these findings describe a unique down-modulation or non-fitness status of the immune response in cervical cancer, the understanding of which will be important for the design of novel immunotherapies against this disease.

ß-Caryophyllene, a Dietary Cannabinoid, Protects Against Metabolic and Immune Dysregulation in a Diet-Induced Obesity Mouse Model.

Obesity is an abnormal or excessive accumulation of fat in the body that exacerbates metabolic and inflammatory processes, and impairs the health of afflicted individuals. ß-caryophyllene is a natural sesquiterpene that is a dietary cannabinoid with anti-inflammatory properties and potential activity against metabolic diseases. In the present study, we evaluated the effect of ß-caryophyllene on C57BL/6 mice using a diet-induced obesity model. Male mice were randomly assigned to the following groups over a 16-week period: (1) standard diet as lean control, (2) high-fat diet (HFD) as obese control, and (3) HFD + ß-caryophyllene with ß-caryophyllene at 50 mg/kg. Treatment with ß-caryophyllene improved various metabolic parameters including increased total body weight, fasting glucose levels, oral-glucose tolerance, insulin tolerance, fasting triglycerides, adipocyte hypertrophy, and liver macrovesicular steatosis. ß-caryophyllene also modulated the levels and expression of immune response factors including adiponectin, leptin, insulin, interleukin-6, tumor necrosis factor-a, and Toll-like receptor-4. Our data indicate that chronic supplementation with ß-caryophyllene can improve relevant metabolic and immunological processes in obese mice. This protocol was approved by the Institutional Committee for Care and Use of Laboratory Animals from the University of Guadalajara with protocol code CUCEI/CINV/CICUAL-01/2022.

Probiotics: Protecting Our Health from the Gut.

The gut microbiota (GM) comprises billions of microorganisms in the human gastrointestinal tract. This microbial community exerts numerous physiological functions. Prominent among these functions is the effect on host immunity through the uptake of nutrients that strengthen intestinal cells and cells involved in the immune response. The physiological functions of the GM are not limited to the gut, but bidirectional interactions between the gut microbiota and various extraintestinal organs have been identified. These interactions have been termed interorganic axes by several authors, among which the gut-brain, gut-skin, gut-lung, gut-heart, and gut-metabolism axes stand out. It has been shown that an organism is healthy or in homeostasis when the GM is in balance. However, altered GM or dysbiosis represents a critical factor in the pathogenesis of many local and systemic diseases. Therefore, probiotics intervene in this context, which, according to various published studies, allows balance to be maintained in the GM, leading to an individual's good health.

In Vivo Healthy Benefits of Galacto-Oligosaccharides from Lupinus albus (LA-GOS) in Butyrate Production through Intestinal Microbiota.

Animal digestive systems host microorganism ecosystems, including integrated bacteria, viruses, fungi, and others, that produce a variety of compounds from different substrates with healthy properties. Among these substrates, α-galacto-oligosaccharides (GOS) are considered prebiotics that promote the grow of gut microbiota with a metabolic output of Short Chain Fatty Acids (SCFAs). In this regard, we evaluated Lupinus albus GOS (LA-GOS) as a natural prebiotic using different animal models. Therefore, the aim of this work was to evaluate the effect of LA-GOS on the gut microbiota, SCFA production, and intestinal health in healthy and induced dysbiosis conditions (an ulcerative colitis (UC) model). Twenty C57BL/6 mice were randomly allocated in four groups (n = 5/group): untreated and treated non-induced animals, and two groups induced with 2% dextran sulfate sodium to UC with and without LA-GOS administration (2.5 g/kg bw). We found that the UC treated group showed a higher goblet cell number, lower disease activity index, and reduced histopathological damage in comparison to the UC untreated group. In addition, the abundance of positive bacteria to butyryl-CoA transferase in gut microbiota was significantly increased by LA-GOS treatment, in healthy conditions. We measured the SCFA production with significant differences in the butyrate concentration between treated and untreated healthy groups. Finally, the pH level in cecum feces was reduced after LA-GOS treatment. Overall, we point out the in vivo health benefits of LA-GOS administration on the preservation of the intestinal ecosystem and the promotion of SCFA production.

Macrophage migration inhibitory factor gene polymorphisms (SNP -173 G>C and STR-794 CATT5-8) confer risk of plaque psoriasis: A case-control study.

BACKGROUND: Macrophage inhibitory factor (MIF) is a pro-inflammatory cytokine secreted by several cells, including those in the immune system and the skin. The MIF gene contains the SNP -173 G> C and STR -794 CATT5-8 polymorphisms in the promoter region capable of affecting its activity. Our objective was to investigate the MIF polymorphisms as a risk factor for plaque psoriasis (PP) in the Mexican population. METHODS: We genotyped both MIF polymorphism (rs5844572 and rs755622) in 224 PP patients with a clinical and histopathological diagnosis and 232 control subjects (CS) by the PCR-RFLP method. MIF serum levels were determined by an ELISA kit. RESULTS: We found significant differences in the genotypic and allelic frequencies for the MIF -173 G>C polymorphism; carriers of the GC genotype (OR 1.51, 95% CI 1.026-2.228, p = 0.03) and the C allele (OR 1.34, 95% CI 1.005-1.807, p = 0.04) had higher odds to present with PP. Moreover, the 6C haplotype was associated with PP risk (OR 2.10, 95% CI 1.22-3.69, p < 0.01). Also, the -173 CC genotype was associated with high MIF serum levels (p < 0.05). CONCLUSIONS: The -173 GC genotype and the 6C haplotype of the MIF polymorphisms are associated with susceptibility to PP in the Mexican population.

To Trap a Pathogen: Neutrophil Extracellular Traps and Their Role in Mucosal Epithelial and Skin Diseases.

Neutrophils are the most abundant circulating innate immune cells and comprise the first immune defense line, as they are the most rapidly recruited cells at sites of infection or inflammation. Their main microbicidal mechanisms are degranulation, phagocytosis, cytokine secretion and the formation of extracellular traps. Neutrophil extracellular traps (NETs) are a microbicidal mechanism that involves neutrophil death. Since their discovery, in vitro and in vivo neutrophils have been challenged with a range of stimuli capable of inducing or inhibiting NET formation, with the objective to understand its function and regulation in health and disease. These networks composed of DNA and granular components are capable of immobilizing and killing pathogens. They comprise enzymes such as myeloperoxidase, elastase, cathepsin G, acid hydrolases and cationic peptides, all with antimicrobial and antifungal activity. Therefore, the excessive formation of NETs can also lead to tissue damage and promote local and systemic inflammation. Based on this concept, in this review, we focus on the role of NETs in different infectious and inflammatory diseases of the mucosal epithelia and skin.

Association between rs662 (A > G) and rs854560 (A > T) polymorphisms in PON1 gene and the susceptibility for psoriasis in mestizo population of Western Mexico.

Psoriasis is a chronic, autoimmune skin disease. In psoriasis, PON1 activity is diminished and peroxidation biomarkers are elevated. The most studied PON1 polymorphisms are rs662 (A > G) and rs854560 (A > T), which have been associated with the antioxidant activity of PON1, risk of cardiovascular diseases and psoriasis development. The aim of this study, was to determine the association of rs662 (A > G) and rs854560 (A > T) PON1 polymorphisms with psoriasis susceptibility in Western Mexico population. In this case-control study, we included 104 psoriasis patients and 124 control subjects. The genotyping of polymorphisms rs662 (A > G) and rs854560 (A > T) of PON1 was carried out by PCR-RFLPs. The lipid profiles were quantified by enzymatic colorimetric method, and PON1 activity was determined by spectrophotometry. The lipid profile levels, except HDL-C and atherogenic index, were higher in patients vs. controls. Patients presented lower paraoxonase and arylesterase activity. The G allele of rs662 (A > G) is associated with risk for psoriasis, while the T allele of rs854560 (A > T) is associated with low susceptibility to psoriasis. The AG haplotype was more frequent within the patient group (p < 0.05). The AA and AG genotypes of rs662 (A > G) and TT and AA genotypes of rs854560 (A > T) are associated with lower PONase and ARE activity in patients vs. controls. Patients with the G allele of rs662 (G > A) and T alleles of rs854560 (A > T) show significant differences in the lipid levels in comparison to controls. These results suggest that carriers of G allele of rs662 (A > G) present a greater susceptibility to psoriasis.

Physiological concentrations of short-chain fatty acids induce the formation of neutrophil extracellular traps in vitro.

Neutrophils represent the first line of host cellular defense against various pathogens. The most recently described microbicidal mechanism of these cells is the release of neutrophil extracellular traps (NET). Currently, a wide range of chemical and biological stimuli are known to induce this response; however, the effect of short-chain fatty acids (SCFAs) on the induction of NET is still unknown. SCFAs are produced mainly by bacterial fermentation of dietary fiber and are found in host tissues and blood. This study aimed to determine whether physiological levels of SCFAs can induce the formation of NET. Previously reported concentrations of SCFAs (as found in the colonic lumen and peripheral blood in postprandial and basal states) were used to stimulate the neutrophils. In order to determine the signaling pathway utilized by SCFAs, we tested the inhibition of the Free Fatty Acid 2 Receptor (FFA2R) expressed in neutrophils using CATPB, the inhibitor of FFA2R, genistein, an inhibitor of the downstream Gα/q11 proteins and DPI, an inhibitor of the NADPH oxidase complex. The SCFAs at colonic intestinal lumen concentrations were able to induce the formation of NET, and when tested at concentrations found in the peripheral blood, only acetic acid at 100 µM (fasting equivalent) and 700 µM (postprandial equivalent) was found to induce the formation of NET. The administration of the competitive inhibitor against the receptor or blockade of relevant G protein signaling and the inhibition of NADPH oxidase complex decreased NET release. SCFAs stimulate NET formation in vitro and this effect is mediated, in part, by the FFA2R.

Lactobacillus reuteri DSM 17938 and Agave Inulin in Children with Cerebral Palsy and Chronic Constipation: A Double-Blind Randomized Placebo Controlled Clinical Trial.

The main objective was to assess the efficacy of a probiotic (Lactobacillus reuteri DSM 17938), a prebiotic (agave inulin), and a synbiotic on the stool characteristics in children with cerebral palsy and chronic constipation. Thirty-seven children with cerebral palsy and chronic constipation were included. The probiotic group received 1 × 108 colony forming unit (cfu) of L. reuteri DSM 17938 plus placebo, the prebiotic group received 4 g of agave inulin plus placebo, the synbiotic group received L. reuteri DSM 17938 plus agave inulin, and the placebo group received two placebos for 28 days. The probiotic group showed a significant decrease in stool pH (p = 0.014). Stool consistency improved in the prebiotic group (p = 0.008). The probiotic, prebiotic, and synbiotic groups showed a significant improvement in the history of excessive stool retention, the presence of fecal mass in the rectum, and the history of painful defecation. L. reuteri concentration in feces was higher in the probiotic group than in the placebo group (p = 0.001) and showed an inverse correlation with stool pH in the probiotic group (r = -0.762, p = 0.028). This study showed that the use of L. reuteri DSM 17938 and/or agave inulin improved the stool characteristics such as the history of painful defecation and the presence of fecal mass in the rectum against placebo in children with cerebral palsy and chronic constipation.

Macrophage inhibitory factor (MIF) gene polymorphisms are associated with disease susceptibility and with circulating MIF levels in active non-segmental vitiligo in patients from western Mexico.

BACKGROUND: The macrophage migration inhibiting factor (MIF) is a protein that promotes the activation of immune cells and the production of other proinflammatory cytokines such as TNF-α, IL-1ß, and IFN-γ, which have proposed to play an essential role in the pathogenesis of vitiligo. The study aimed to assess the association between MIF polymorphisms (-794 CATT5-8 and -173 G>C), MIF in situ expression, and MIF serum concentrations with susceptibility and disease activity in patients with non-segmental vitiligo (NSV) from western Mexico. METHODS: The study included 111 patients with NSV and 201 control subjects. Genotyping was performed by conventional PCR (-794 CATT5-8 ) and PCR-RFLP (-173 G>C) methods. MIF mRNA expression was quantified by real-time PCR and MIF serum concentrations were determined by ELISA kit. Histopathological samples were analyzed by automated immunohistochemistry. RESULTS: The MIF polymorphisms were associated with NSV susceptibility. Serum concentrations of MIF were higher in patients with active NSV and correlated negatively with the years of evolution. The depigmented skin from patients with active vitiligo showed a high expression of MIF. CONCLUSION: MIF polymorphisms increase the risk of NSV in the western Mexican population. The serum concentrations of MIF and in situ expression are associated with active NSV.

Adenovirus Biodistribution is Modified in Sensitive Animals Compared to Naïve Animals.

Pre-existing immune response against adenovirus could diminish transgene expression efficiency when Ad is employed in humans as gene therapy vector. We previously used Ad-hΔuPA (Recombinant adenovirus expressing human urokinase-type plasminogen activator) as antifibrotic gene therapy in cirrhosis models and demonstrated its effectiveness. As a further clinical approach, transient Cyclosporine A (CsA) immunosuppression was induced in cirrhotic animals to determine whether Ad-hΔuPA administration retained efficacy. Adenovirus sensitization was achieved by systemic administration of non-therapeutic Ad-ßGal (Recombinant adenovirus expressing beta-galactosidase) after 4 weeks of intraperitoneal carbon tetrachloride (CCl4) regimen. Cirrhosis induction continued up to 8 weeks. At the end of CCl4 intoxication, immunosuppression was achieved with three CsA doses (40 mg/kg) as follows: 24 h before administration of Ad-hΔuPA, at the moment of Ad-hΔuPA injection and finally, 24 h after Ad-hΔuPA inoculation. At 2 and 72 h after Ad-hΔuPA injection, animals were sacrificed. Liver, spleen, lung, kidney, heart, brain, and testis were analyzed for Ad-biodistribution and transgene expression. In naïve animals, Ad-hΔuPA genomes prevailed in liver and spleen, while Ad-sensitized rats showed Ad genomes also in their kidney and heart. Cirrhosis and Ad preimmunization status notably diminished transgene liver expression compared to healthy livers. CsA immunosuppression in cirrhotic animals has no effect on Ad-hΔuPA biodistribution, but increments survival.

Microbiota and Its Role on Viral Evasion: Is It With Us or Against Us?

Viruses are obligate intracellular pathogens that require the protein synthesis machinery of the host cells to replicate. These microorganisms have evolved mechanisms to avoid detection from the host immune innate and adaptive response, which are known as viral evasion mechanisms. Viruses enter the host through skin and mucosal surfaces that happen to be colonized by communities of thousands of microorganisms collectively known as the commensal microbiota, where bacteria have a role in the modulation of the immune system and maintaining homeostasis. These bacteria are necessary for the development of the immune system and to prevent the adhesion and colonization of bacterial pathogens and parasites. However, the interactions between the commensal microbiota and viruses are not clear. The microbiota could confer protection against viral infection by priming the immune response to avoid infection, with some bacterial species being required to increase the antiviral response. On the other hand, it could also help to promote viral evasion of certain viruses by direct and indirect mechanisms, with the presence of the microbiota increasing infection and viruses using LPS and surface polysaccharides from bacteria to trigger immunosuppressive pathways. In this work, we reviewed the interaction between the microbiota and viruses to prevent their entry into host cells or to help them to evade the host antiviral immunity. This review is focused on the influence of the commensal microbiota in the viruses' success or failure of the host cells infection.

Analysis of the rs2476601 polymorphism of PTPN22 in Mexican mestizo patients with leprosy.

Leprosy, a human chronic granulomatous disease caused by Mycobacterium leprae (M. leprae), remains endemic in certain countries despite the use of multidrug therapy. Recently, several host genes modulating the immune responses to M. leprae infection have been suggested to influence the acquisition and clinical course of leprosy. Lymphoid protein tyrosine phosphatase, encoded by the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, serves a negative regulatory role in T cell activation. The non-synonymous single-nucleotide polymorphism (SNP) rs2476601 (1858C>T) has been associated with autoimmune diseases. Here, the present study investigated if rs2476601 polymorphism was associated with leprosy in a Mexican mestizo population. Genotyping was performed in patients with leprosy (n=189) and control subjects (n=231) from regions with higher incidence of leprosy. Genotypic (P=0.44) and allelic frequencies (P=0.45) of the rs2476601 polymorphism were similar between patients and controls; genotypic frequencies were 91 vs. 94% for CC and 9 vs. 6% for CT, and the TT genotype was absent in both groups. Allelic frequencies were 96 vs. 97% for C, and 4 vs. 3% for T. In the same way, the genotypic (P=0.46) and allelic frequencies (P=0.47) from MB patients and controls were similar. In conclusion, there was a lack of association of the PTPN22 rs2476601 polymorphism with the development of leprosy, which suggests that this SNP was not a genetic risk factor for leprosy in the Mexican mestizo population studied.

Serum Levels of Migration Inhibitory Factor (MIF) and In Situ Expression of MIF and Its Receptor CD74 in Lepromatous Leprosy Patients: A Preliminary Report.

Leprosy is a chronic disease caused by Mycobacterium leprae that affects the skin and peripheral nerves. It may present as one of two distinct poles: the self-limiting tuberculoid leprosy and the highly infectious lepromatous leprosy (LL) characterized by M. leprae-specific absence of cellular immune response. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) enhance the bactericide activities of macrophages after interaction with its receptor, CD74. Importantly, MIF also possesses chemoattractant properties, and it is a key factor in situ for the activation of macrophages and in blood to promote leukocytes migration. MIF-mediated activation of macrophages is a key process for the elimination of pathogens such as Mycobacterium tuberculosis; however, its participation for the clearance of M. leprae is unclear. The aim of this study was to evaluate the serum levels of MIF as well as MIF and CD74 expression in skin lesions of LL and compare it with healthy skin (HSk) taken from subjects attending to dermatological consult. Samples of serum and skin biopsies were taken from 39 LL patients and compared with 36 serum samples of healthy subjects (HS) and 10 biopsies of HSk. Serum samples were analyzed by ELISA and skin biopsies by immunohistochemistry (IHC). IHC smears were observed in 12 100× microscopic fields, in which percentage of stained cells and staining intensity were evaluated. Both variables were used to calculate a semi-quantitative expression score that ranged from 0 to 3+. We found no differences in MIF levels between LL patients and HS in sera. In addition, MIF was observed in over 75% of cells with high intensity in the skin of patients and HSk. Although we found no differences in MIF expression between the groups, a CD74 score statistically higher was found in LL skin than HSk (p < 0.001); this was the result of a higher percentage of cells positive for CD74 (p < 0.001). As a conclusion, we found that CD74-positive cells are intensely recruited to the skin with LL lesions. In this manner, MIF signaling may be enhanced in the skin of LL patients due to increased expression of its receptor, but further studies are required.

Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview.

In addition to physical barriers, neutrophils are considered a part of the first line of immune defense. They can be found in the bloodstream, with a lifespan of 6-8 h, and in tissue, where they can last up to 7 days. The mechanisms that neutrophils utilize for host defense are phagocytosis, degranulation, cytokine production, and, the most recently described, neutrophil extracellular trap (NET) production. NETs are DNA structures released due to chromatin decondensation and spreading, and they thus occupy three to five times the volume of condensed chromatin. Several proteins adhere to NETs, including histones and over 30 components of primary and secondary granules, among them components with bactericidal activity such as elastase, myeloperoxidase, cathepsin G, lactoferrin, pentraxin 3, gelatinase, proteinase 3, LL37, peptidoglycan-binding proteins, and others with bactericidal activity able to destroy virulence factors. Three models for NETosis are known to date. (a) Suicidal NETosis, with a duration of 2-4 h, is the best described model. (b) In vital NETosis with nuclear DNA release, neutrophils release NETs without exhibiting loss of nuclear or plasma membrane within 5-60 min, and it is independent of reactive oxygen species (ROS) and the Raf/MERK/ERK pathway. (c) The final type is vital NETosis with release of mitochondrial DNA that is dependent on ROS and produced after stimuli with GM-CSF and lipopolysaccharide. Recent research has revealed neutrophils as more sophisticated immune cells that are able to precisely regulate their granular enzymes release by ion fluxes and can release immunomodulatory cytokines and chemokines that interact with various components of the immune system. Therefore, they can play a key role in autoimmunity and in autoinflammatory and metabolic diseases. In this review, we intend to show the two roles played by neutrophils: as a first line of defense against microorganisms and as a contributor to the pathogenesis of various illnesses, such as autoimmune, autoinflammatory, and metabolic diseases.