The antimicrobial peptide LL‐37 modulates the inflammatory and host defense response of human neutrophils

The human cathelicidin antimicrobial peptide acts as an effector molecule of the innate immune system with direct antimicrobial and immunomodulatory effects. The aim of this study was to test whether the cathelicidin LL‐37 modulates the response of neutrophils to microbial stimulation. Human neutrophils were exposed to LPS, Staphylococcus aureus and Pseudomonas aeruginosa subsequent to incubation with LL‐37 and cytokine release was measured by ELISA. The incubation with LL‐37 significantly decreased the release of proinflammatory cytokines from stimulated human neutrophils. ROS production of neutrophils was determined by a luminometric and a flow cytometry method. The peptide induced the production of ROS and the engulfment of bacteria into neutrophils. Peritoneal mouse neutrophils isolated from CRAMP‐deficient and WT animals were treated with LPS and TNF‐α in the supernatant was measured by ELISA. Antimicrobial activity of neutrophils was detected by incubating neutrophils isolated from CRAMP‐knockout and WT mice with bacteria. Neutrophils from CRAMP‐deficient mice released significantly more TNF‐α after bacterial stimulation and showed decreased antimicrobial activity as compared to cells from WT animals. In conclusion, LL‐37 modulates the response of neutrophils to bacterial activation. Cathelicidin controls the release of inflammatory mediators while increasing antimicrobial activity of neutrophils.     

Bacterial subversion of cAMP signalling inhibits cathelicidin expression,which is required for innate resistance to Mycobacterium tuberculosis

Antimicrobial peptides such as cathelicidins are important components of innate immune defence against inhaled microorganisms, and have shown antimicrobial activity against Mycobacterium tuberculosis in in vitro models. Despite this, little is known about the regulation and expression of cathelicidin during tuberculosis in vivo. We sought to determine whether the cathelicidin‐related antimicrobial peptide gene (Cramp), the murine functional homologue of the human cathelicidin gene (CAMP or LL‐37), is required for regulation of protective immunity during M. tuberculosis infection in vivo. We used Cramp^–/– mice in a validated model of pulmonary tuberculosis, and conducted cell‐based assays with macrophages from these mice. We evaluated the in vivo susceptibility of Cramp^–/– mice to infection, and also dissected various pro‐inflammatory immune responses against M. tuberculosis. We observed increased susceptibility of Cramp^–/– mice to M. tuberculosis as compared with wild‐type mice. Macrophages from Cramp^–/– mice were unable to control M. tuberculosis growth in an in vitro infection model, were deficient in intracellular calcium influx, and were defective in stimulating T cells. Additionally, CD4⁺ and CD8⁺ T cells from Cramp^–/– mice produced less interferon‐β upon stimulation. Furthermore, bacterial‐derived cAMP modulated cathelicidin expression in macrophages. Our results demonstrate that cathelicidin is required for innate resistance to M. tuberculosis in a relevant animal model and is a key mediator in regulation of the levels of pro‐inflammatory cytokines by calcium and cyclic nucleotides. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The antimicrobial activity of the cathelicidin LL37 is inhibited by F-actin bundles and restored by gelsolin

Antimicrobial peptides are part of the innate host defense system, and inactivation of these peptides is implicated in airway infections in cystic fibrosis (CF). The sputum of patients with CF contains anionic polyelectrolytes, including F-actin and DNA not found in normal airway fluid. These anionic filaments aggregate to contribute to the altered viscoelastic properties of CF sputum. We hypothesized that the airway components stabilizing bundles of F-actin and DNA are in part cationic antimicrobial agents, and that appropriate modification of diseased airway fluid of patients with CF might dissociate these bundles and restore antimicrobial activity. We demonstrate that the human cathelicidin peptide LL37 forms bundles with F-actin and DNA, which are dissolved by gelsolin and DNase, respectively. Coincident with bundle formation, antimicrobial activity of LL37 is inhibited by F-actin and DNA. Pseudomonas bacteria were killed by low concentrations of LL37, but killing was significantly reduced in the presence of F-actin. The actin filament-fragmenting protein gelsolin restored bactericidal activity nearly completely. In a growth inhibition assay, the effects of F-actin were confirmed, and DNA was also shown to inhibit the activity of LL37. When added to CF sputum, gelsolin significantly reduced the growth of bacteria, suggesting activation of endogenous antimicrobial factors. These findings may have therapeutic implications for treatments previously thought to alter only the viscoelastic properties of airway secretions and amplify the possible advantage of gelsolin in CF treatment.     

CD40 ligand and interferon‐γ induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes

The ability of T cells to activate antimicrobial pathways in infected macrophages is essential to host defence against many intracellular pathogens. Here, we compared the ability of two T‐cell‐mediated mechanisms to trigger antimicrobial responses against Mycobacterium tuberculosis in humans, CD40 activation and the release of interferon‐γ (IFN‐γ). Given that IFN‐γ activates a vitamin D‐dependent antimicrobial response, we focused on induction of the key components of this pathway. We show that activation of human monocytes via CD40 ligand (CD40L) and IFN‐γ, alone, and in combination, induces the CYP27b1‐hydroxylase, responsible for the conversion of 25‐hydroxyvitamin D (25D) to the bioactive 1,25‐dihydroxyvitamin D (1,25D), and the vitamin D receptor (VDR). The activation of the vitamin D pathway by CD40L and IFN‐γ results in up‐regulated expression of the antimicrobial peptides, cathelicidin and DEFB4, as well as induction of autophagy. Finally, activation of monocytes via CD40L and IFN‐γ results in an antimicrobial activity against intracellular M. tuberculosis. Our data suggest that at least two parallel T‐cell‐mediated mechanisms, CD40L and IFN‐γ, activate the vitamin D‐dependent antimicrobial pathway and trigger antimicrobial activity against intracellular M. tuberculosis, thereby contributing to human host defence against intracellular infection.     

Human cathelicidin LL‐37 and its derivative IG‐19 regulate interleukin‐32‐induced inflammation

Human cathelicidin LL‐37 protects against infections and endotoxin‐induced inflammation. In a recent study we have shown that IG‐19, an LL‐37‐derived peptide, protects in a murine model of arthritis. Cytokine interleukin‐32 (IL‐32) is elevated and directly associated with the disease severity of inflammatory arthritis. Therefore, in this study we examined the effects of LL‐37 and IG‐19 on IL‐32‐induced responses in human peripheral blood‐derived mononuclear cells (PBMC) and macrophages. We showed that CD14⁺ monocytes are the primary cells that produce pro‐inflammatory tumour necrosis factor‐α (TNF‐α) following stimulation of PBMC with IL‐32. We demonstrated that LL‐37 and IG‐19 significantly suppress IL‐32‐induced production of pro‐inflammatory cytokines, e.g. TNF‐α and IL‐1β, without altering chemokine production. In contrast, LL‐37 and IG‐19 enhance the production of the anti‐inflammatory cytokine IL‐1RA. Further mechanistic studies revealed that LL‐37 and IG‐19 suppress IL‐32‐mediated phosphorylation of Fyn (Y420) Src kinase. In contrast, IL‐32‐mediated phosphorylation of AKT‐1 (T308) and MKP‐1 (S359) is not suppressed by the peptides. LL‐37 and IG‐19 alone induce the phosphorylation of MKP‐1 (S359), which is a known negative regulator of inflammation. Furthermore, the peptides induce the activity of p44/42 mitogen‐activated protein kinase, which is known to phosphorylate MKP‐1 (S359). This is the first study to demonstrate the regulation of IL‐32‐induced inflammation by LL‐37 and its derivative peptide IG‐19. The mechanistic results from this study suggest that regulation of immune‐mediated inflammation by these peptides may be controlled by the dual phosphatase MKP‐1. We speculate that LL‐37 and its derivatives may contribute to the control of immune‐mediated inflammatory diseases.     

Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease

Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA‐rich mucus plugs are characteristic features of severe RSV–LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first‐line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti‐viral effect in vitro. Second, we studied NET formation in vivo during severe RSV–LRTD in infants and bovine RSV–LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV–LRTD. Detailed histopathological examination of calves with RSV–LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV–LRTD contributes to airway obstruction. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Human γδ T Cells Produce the Protease Inhibitor and Antimicrobial Peptide Elafin

Human γδ T cells rapidly secrete pro-inflammatory cytokines in response to T cell receptor-dependent recognition of pyrophosphates produced by many bacteria and parasites. In further support of an important role of γδ T cells in the immune defence against infection, human γδ T cells have been shown to produce the antimicrobial peptide LL37/cathelicidin. In this study, we have investigated whether γδ T cells can produce additional antimicrobial peptides. To this end, we have screened human γδ T cell clones by RT-PCR for mRNA expression of a broad range of antimicrobial peptides. While α-defensins were absent and β-defensins (HBD1) present only in rare γδ T cell clones, elafin mRNA was induced by supernatant of Pseudomonas aeruginosa grown under static conditions. Elafin is a protease inhibitor that also displays antimicrobial activity. Constitutive intracellular expression of elafin was demonstrated by flow cytometry and Western blot analysis. Furthermore, trappin-2 (pre-elafin) could be immunoprecipitated in cell lysates but also in the supernatant of γδ T cells stimulated by Ps. aeruginosa supernatant. Taken together, our studies reveal a novel effector function of γδ T cells which might be important for local immune defence.     

Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37

Recent in vivo studies indicate that mesenchymal stem cells (MSCs) may have beneficial effects in the treatment of sepsis induced by bacterial infection. Administration of MSCs in these studies improved survival and enhanced bacterial clearance. The primary objective of this study was to test the hypothesis that human MSCs possessed intrinsic antimicrobial properties. We studied the effect of human MSCs derived from bone marrow on the bacterial growth of Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria. MSCs as well as their conditioned medium (CM) demonstrated marked inhibition of bacterial growth in comparison with control medium or normal human lung fibroblasts (NHLF). Analysis of expression of major antimicrobial peptides indicated that one of the factors responsible for the antimicrobial activity of MSC CM against Gram-negative bacteria was the human cathelicidin antimicrobial peptide, hCAP-18/LL-37. Both m-RNA and protein expression data showed that the expression of LL-37 in MSCs increased after bacterial challenge. Using an in vivo mouse model of E. coli pneumonia, intratracheal administration of MSCs reduced bacterial growth (in colony-forming unit) in the lung homogenates and in the bronchoalveolar lavage (BAL) fluid, and administration of MSCs simultaneously with a neutralizing antibody to LL-37 resulted in a decrease in bacterial clearance. In addition, the BAL itself from MSC-treated mice had a greater antimicrobial activity in comparison with the BAL of phosphate buffered saline (PBS)-treated mice. Human bone marrow-derived MSCs possess direct antimicrobial activity, which is mediated in part by the secretion of human cathelicidin hCAP-18/ LL-37.     

Expression of cathelicidin LL-37 during Mycobacterium tuberculosis infection in human alveolar macrophages, monocytes, neutrophils, and epithelial cells

The innate immune response in human tuberculosis is not completely understood. To improve our knowledge regarding the role of cathelicidin hCAP-18/LL37 in the innate immune response to tuberculosis infection, we used immunohistochemistry, immunoelectron microscopy, and gene expression to study the induction and production of the antimicrobial peptide in A549 epithelial cells, alveolar macrophages (AM), neutrophils, and monocyte-derived macrophages (MDM) after infection with Mycobacterium tuberculosis. We demonstrated that mycobacterial infection induced the expression and production of LL-37 in all cells studied, with AM being the most efficient. We did not detect peptide expression in tuberculous granulomas, suggesting that LL-37 participates only during early infection. Through the study of Toll-like receptors (TLR) in MDM, we showed that LL-37 can be induced by stimulation through TLR-2, TLR-4, and TLR-9. This last TLR was strongly stimulated by M. tuberculosis DNA. We concluded that LL-37 may have an important role in the innate immune response against M. tuberculosis.     

Evidence that cathelicidin peptide LL‐37 may act as a functional ligand for CXCR2 on human neutrophils

LL‐37, derived from human cathelicidin, stimulates immune responses in neutrophils. Although FPR2 and P2X7 were proposed as LL‐37 receptors, we have shown that among 21 neutrophil receptors only CXCR2 was down‐regulated by LL‐37. LL‐37 functions similarly to CXCR2‐specific chemokines CXCL1 and CXCL7 in terms of receptor down‐regulation and intracellular calcium mobilization on freshly isolated neutrophils. Neutrophils pretreated with CXCL8, a chemokine that binds both CXCR1/2, completely blocked the calcium mobilization in response to LL‐37, while LL‐37 also partially inhibited ¹²⁵I‐CXCL8 binding to neutrophils. SB225002, a selective CXCR2 antagonist, blocked LL‐37‐induced calcium mobilization and migration of neutrophils. LL‐37 stimulates calcium mobilization in CXCR2‐transfected HEK293 cells, CXCR2⁺ THP‐1 cells and monocytes, but not in CXCR1‐transfected HEK293 cells. WKYMVm peptide (ligand for FPR2) does not block LL‐37‐stimulated calcium flux in either THP‐1 (FPR2^?) or monocytes (FPR2^high), further confirming the specificity of LL‐37 for CXCR2 and not FPR2. Among all ligands tested (ATP, BzATP, WKYMVm, CXCL1, and LL‐37), only LL‐37 stimulated migration of monocytes (CXCR2⁺ and FPR2⁺) and migration was inhibited by the CXCR2 inhibitor SB225002. Moreover, CXCR2 but not CXCR1 was internalized in LL‐37‐treated neutrophils. Thus, our data provide evidence that LL‐37 may act as a functional ligand for CXCR2 on human neutrophils.     

Cationic antimicrobial peptides in psoriatic skin cooperate to break innate tolerance to self‐DNA

Psoriasis is a T‐cell‐mediated skin autoimmune disease characterized by the aberrant activation of dermal dendritic cells (DCs) and the sustained epidermal expression of antimicrobial peptides. We have previously identified a link between these two events by showing that the cathelicidin antimicrobial peptide LL37 has the ability to trigger self‐nucleic acid mediated activation of plasmacytoid DCs (pDCs) in psoriatic skin. Whether other cationic antimicrobial peptides exert similar activities is unknown. By analyzing heparin‐binding HPLC fractions of psoriatic scales, we found that human beta‐defensin (hBD)2, hBD3, and lysozyme are additional triggers of pDC activation in psoriatic skin lesions. Like LL37, hBD2, hBD3, and lysozyme are able to condense self‐DNA into particles that are endocytosed by pDCs, leading to activation of TLR9. In contrast, other antimicrobial peptides expressed in psoriatic skin including elafin, hBD1, and psoriasin (S100A7) did not show similar activities. hBD2, hBD3, and lysozyme were detected in psoriatic skin lesions in the vicinity of pDCs and found to cooperate with LL37 to induce high levels of IFN production by pDCs, suggesting their concerted role in the pathogenesis of psoriasis.     

Augmentation of Innate Host Defense by Expression of a Cathelicidin Antimicrobial Peptide

Antimicrobial peptides, such as defensins or cathelicidins, are effector substances of the innate immune system and are thought to have antimicrobial properties that contribute to host defense. The evidence that vertebrate antimicrobial peptides contribute to innate immunity in vivo is based on their expression pattern and in vitro activity against microorganisms. The goal of this study was to investigate whether the overexpression of an antimicrobial peptide results in augmented protection against bacterial infection. C57BL/6 mice were given an adenovirus vector containing the cDNA for LL-37/hCAP-18, a human cathelicidin antimicrobial peptide. Mice treated with intratracheal LL-37/hCAP-18 vector had a lower bacterial load and a smaller inflammatory response than did untreated mice following pulmonary challenge with Pseudomonas aeruginosa PAO1. Systemic expression of LL-37/hCAP-18 after intravenous injection of recombinant adenovirus resulted in improved survival rates following intravenous injection of lipopolysaccharide with galactosamine or Escherichia coli CP9. In conclusion, the data demonstrate that expression of an antimicrobial peptide by gene transfer results in augmentation of the innate immune response, providing support for the hypothesis that vertebrate antimicrobial peptides protect against microorganisms in vivo.     

Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages

Control of tuberculosis worldwide depends on our understanding of human immune mechanisms, which combat the infection. Acquired T cell responses are critical for host defense against microbial pathogens, yet the mechanisms by which they act in humans remain unclear. We report that T cells, by the release of interferon-γ (IFN-γ), induce autophagy, phagosomal maturation, the production of antimicrobial peptides such as cathelicidin, and antimicrobial activity against Mycobacterium tuberculosis in human macrophages via a vitamin D-dependent pathway. IFN-γ induced the antimicrobial pathway in human macrophages cultured in vitamin D-sufficient sera, but not in sera from African-Americans that have lower amounts of vitamin D and who are more susceptible to tuberculosis. In vitro supplementation of vitamin D-deficient serum with 25-hydroxyvitamin D3 restored IFN-γ-induced antimicrobial peptide expression, autophagy, phagosome-lysosome fusion, and antimicrobial activity. These results suggest a mechanism in which vitamin D is required for acquired immunity to overcome the ability of intracellular pathogens to evade macrophage-mediated antimicrobial responses. The present findings underscore the importance of adequate amounts of vitamin D in all human populations for sustaining both innate and acquired immunity against infection.     

Cathelicidin Antimicrobial Peptide LL‐37 in Cholesteatoma Enables Keratinocyte Reactivity with Cytosolic DNA

The purpose of this study was to determine whether self‐DNA can trigger the inflammatory response in cholesteatoma. Specimens were collected from nine patients with invasive cholesteatoma, nine patients with attic‐type cholesteatoma (pars flaccida was perforated in five patients and intact in four) and four healthy skins. Expression and localization of LL‐37 and interferon‐alpha were detected by immunofluorescence and immunoblot analysis. Cultures of human cholesteatomatous keratinocytes were exposed to CpG DNA, LL‐37 or CpG DNA complexed to LL‐37 for 24 h. Expression of interferon‐alpha was detected by RT‐PCR. We detected abundant cytosolic DNA, increased LL‐37 and interferon‐alpha in keratinocytes in invasive cholesteatoma and attic‐type cholesteatoma with pars flaccida perforation, but not in attic‐type cholesteatoma with pars flaccida intact and normal skin. In cultured keratinocytes, LL‐37–DNA complexes induced IFN‐α expression. These data suggest that cytosolic DNA is an important disease‐associated molecular pattern that triggers the inflammation response in cholesteatoma. Furthermore, LL‐37 played an important role in DNA‐triggered inflammation. Thus, we have identified a link between cytosolic DNA, LL‐37 and autoinflammation in cholesteatoma, providing new potential targets for the treatment of this disease.     

Impaired Degradation of Neutrophil Extracellular Traps: A Possible Severity Factor of Elderly Male COVID-19 Patients

Neutrophil extracellular traps (NETs) have been described as a potential trigger of severe COVID-19. NETs are known as extracellular DNA fibers released by neutrophils in response to infection. If the host is unable to balance efficient clearance of NETs by dornases (DNases), detrimental consequences occur. Elevated levels of NETs in COVID-19 patients are associated with higher risk of morbid thrombotic complications. Here, we studied the level of NET markers and DNase activity in a cohort of COVID-19 patients compared to healthy controls. Our data confirmed an increased level of NET markers in the plasma of COVID-19 patients, with a higher level in male compared to female patients. At the same time, there was an increased DNase activity detectable in COVID-19 patients compared to healthy controls. Importantly, there was a negative correlation of DNase activity with the age of male patients. The antimicrobial peptide LL-37, which is known to stabilize NETs against DNase degradation, is embedded in NETs upon severe acute respiratory syndrome coronavirus-2-infection. The LL-37 plasma level correlates with the NET-marker level in male COVID-19 patients, indicating a potential role of LL-37 in the risk of NET-associated thrombosis in male COVID-19 patients by stabilizing NETs against DNase degradation. In conclusion, our data identify two potential risk factors of elderly male patients which may lead to inefficient NET degradation and a subsequently higher risk of NET-associated thrombosis during COVID-19: reduced DNase activity and an increased LL-37 level.     

Keratinocyte production of cathelicidin provides direct activity against bacterial skin pathogens

Immune defense at an interface with the external environment reflects the functions of physical and chemical barriers provided by epithelial and immune cells. Resident epithelial cells, such as keratinocytes, produce numerous peptides with direct antimicrobial activity but also provide a physical barrier against invading pathogens and signal the recruitment of circulating immune cells, such as neutrophils. Antimicrobial peptides such as cathelicidin are produced constitutively by neutrophils and are inducible in keratinocytes in response to infection. The multiplicity of antimicrobial peptides and their cellular sources has resulted in an incomplete understanding of the role of cathelicidin production by epithelial cells in cutaneous immune defense. Therefore, this study sought to evaluate keratinocyte antimicrobial activity and the potential contribution of keratinocyte cathelicidin to host protection against two leading human skin pathogens. Wild-type mice and those with a targeted deletion of the cathelicidin gene, Cnlp, were rendered neutropenic prior to cutaneous infection. Interestingly, Cnlp-deficient mice remained more susceptible to group A streptococcus infection than mice with Cnlp intact, suggesting the involvement of epithelial cell-derived cathelicidin in host immune defense. Keratinocytes were then isolated in culture and found to inhibit the growth of Staphylococcus aureus, an effect that was partially dependent on their ability to synthesize and activate cathelicidin. Further, lentivirus-mediated delivery of activated human cathelicidin enhanced keratinocyte antimicrobial activity. Combined, these data illustrate the potential contribution of keratinocyte cathelicidin to the innate immune defense of skin against bacterial pathogens and highlight the need to consider epithelial antimicrobial function in the diagnosis and therapy of skin infection.     

Bactericidal activity of mammalian cathelicidin-derived peptides

Endogenous antimicrobial peptides of the cathelicidin family contribute to innate immunity. The emergence of widespread antibiotic resistance in many commonly encountered bacteria requires the search for new bactericidal agents with therapeutic potential. Solid-phase synthesis was employed to prepare linear antimicrobial peptides found in cathelicidins of five mammals: human (FALL39/LL37), rabbit (CAP18), mouse (mCRAMP), rat (rCRAMP), and sheep (SMAP29 and SMAP34). These peptides were tested at ionic strengths of 25 and 175 mM against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus. Each peptide manifested activity against P. aeruginosa irrespective of the NaCl concentration. CAP18 and SMAP29 were the most effective peptides of the group against all test organisms under both low- and high-salt conditions. Select peptides of 15 to 21 residues, modeled on CAP18 (37 residues), retained activity against the gram-negative bacteria and methicillin-sensitive S. aureus, although the bactericidal activity was reduced compared to that of the parent peptide. In accordance with the behavior of the parent molecule, the truncated peptides adopted an alpha-helical structure in the presence of trifluoroethanol or lipopolysaccharide. The relationship between the bactericidal activity and several physiochemical properties of the cathelicidins was examined. The activities of the full-length peptides correlated positively with a predicted gradient of hydrophobicity along the peptide backbone and with net positive charge; they correlated inversely with relative abundance of anionic residues. The salt-resistant, antimicrobial properties of CAP18 and SMAP29 suggest that these peptides or congeneric structures have potential for the treatment of bacterial infections in normal and immunocompromised persons and individuals with cystic fibrosis.     

Enhanced formation and impaired degradation of neutrophil extracellular traps in dermatomyositis and polymyositis: a potential contributor to interstitial lung disease complications

Dermatomyositis (DM) and polymyosits (PM) are systemic autoimmune diseases whose pathogeneses remain unclear. Neutrophil extracellular traps (NETs) are reputed to play an important role in the pathogenesis of autoimmune diseases. This study tests the hypothesis that NETs may be pathogenic in DM/PM. Plasma samples from 97 DM/PM patients (72 DM, 25 PM) and 54 healthy controls were tested for the capacities to induce and degrade NETs. Plasma DNase I activity was tested to further explore possible reasons for the incomplete degradation of NETs. Results from 35 DM patients and seven PM patients with interstitial lung disease (ILD) were compared with results from DM/PM patients without ILD. Compared with control subjects, DM/PM patients exhibited a significantly enhanced capacity for inducing NETs, which was supported by elevated levels of plasma LL‐37 and circulating cell‐free DNA (cfDNA) in DM/PM. NETs degradation and DNase I activity were also decreased significantly in DM/PM patients and were correlated positively. Moreover, DM/PM patients with ILD exhibited the lowest NETs degradation in vitro due to the decrease in DNase I activity. DNase I activity in patients with anti‐Jo‐1 antibodies was significantly lower than in patients without. Glucocorticoid therapy seems to improve DNase I activity. Our findings demonstrate that excessively formed NETs cannot be degraded completely because of decreased DNase I activity in DM/PM patients, especially in patients with ILD, suggesting that abnormal regulation of NETs may be involved in the pathogenesis of DM/PM and could be one of the factors that initiate and aggravate ILD.