Complexation of fungal extracellular nucleic acids by host LL-37 peptide shapes neutrophil response to Candida albicans biofilm

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 6, 2024

Candida albicans remains the predominant cause of fungal infections, where adhered microbial cells form biofilms - densely packed communities. The central feature C. is production an extracellular matrix (ECM) consisting polymers and nucleic acids (eDNA, eRNA), which significantly impedes infiltration host cells. Neutrophils, as crucial players in innate defense, employ several mechanisms to eradicate infection, including NETosis, endocytosis, or release granules containing, among others, antimicrobial peptides (AMPs). main representative these positively charged peptide LL-37 formed from inactive precursor (hCAP18). In addition its functions, this possesses a propensity interact with negatively molecules, acids. Our vitro studies have demonstrated that contacting acids, isolated biofilm, are complexed by shorter derivatives, confirmed electrophoretic mobility shift assays. We indicated generation complexes induces discernible alterations neutrophil response compared effects unconjugated molecules. analyses involving fluorescence microscopy, flow cytometry, Western blotting revealed stimulation neutrophils DNA:LL-37 RNA:LL-37 hamper activation pro-apoptotic caspases 3 7 fosters increased anti-apoptotic pathways mediated Mcl-1 protein. Furthermore, formation elicits dual effect on immune response. Firstly, they facilitate acid uptake, evidenced microscopic observations, enhance pro-inflammatory response, promoting IL-8 production. Secondly, detection suppresses reactive oxygen species attenuates NETosis activation. conclusion, findings may imply shifts toward mobilizing system whole, rather than inactivating pathogen locally. shed new light intricate interplay between constituents biofilm host’s indicate possible reasons for elimination arsenal during contact biofilm.

Language: Английский

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Advancements in Diabetic Foot Ulcer Research: Focus on Mesenchymal Stem Cells and Their Exosomes

Heliyon, Journal Year: 2024, Volume and Issue: 10(17), P. e37031 - e37031

Published: Aug. 29, 2024

Diabetes represents a widely acknowledged global public health concern. Diabetic foot ulcer (DFU) stands as one of the most severe complications diabetes, its occurrence imposing substantial economic burden on patients, profoundly impacting their quality life. Despite deepening comprehension regarding pathophysiology and cellular well molecular responses DFU, current therapeutic arsenal falls short efficacy, failing to offer comprehensive remedy for deep-seated chronic wounds microvascular occlusions. Conventional treatments merely afford symptomatic alleviation or retard disease's advancement, devoid capacity effectuate further restitution compromised vasculature nerves. An escalating body research underscores prominence mesenchymal stem cells (MSCs) owing paracrine attributes anti-inflammatory prowess, rendering them focal point in realm wound healing. Presently, MSCs have been validated highly promising approach capable effectuating repair, epithelialization, granulation tissue formation, neovascularization by means targeted differentiation, angiogenesis promotion, immunomodulation, activities, thereby fostering The secretome comprises cytokines, growth factors, chemokines, alongside exosomes harboring mRNA, proteins, microRNAs, possessing immunomodulatory regenerative properties. present study provides systematic exposition etiology DFU elucidates intricate mechanisms diverse functionalities context treatment, furnishing pioneering perspectives aimed at harnessing potential management advancing healing processes.

Language: Английский

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ROS and DNA repair in spontaneous versus agonist-induced NETosis: Context matters

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Nov. 8, 2022

Reactive oxygen species (ROS) is essential for neutrophil extracellular trap formation (NETosis). Nevertheless, how ROS induces NETosis at baseline and during activation unknown. Although neutrophils carry DNA transcription, replication repair machineries, their relevance in the short-lived mature that pre-synthesized proteins has remained a mystery decades. Our recent studies show (i) NETosis-inducing agonists promote NETosis-specific kinase activation, genome-wide transcription helps to decondense chromatin, (ii) excess produced by NADPH oxidase activating generate 8-oxy-guanine (8-OG), initial steps of are needed chromatin these cells. These require necessary assembly nicking damaged sites (poly ADP ribose polymerase PARP, apurinic endonuclease APE1 ligase), but not enzymes mediate synthesis (Proliferating cell nuclear antigen (PCNA) Polymerases). In this study, we similar agonist-induced NETosis, inhibition early oxidative damage suppresses spontaneous late stage polymerases PCNA drastically promotes NETosis. Hence, absence excessive generation mediated prevent decondensation findings indicate ROS, damage, differentially regulate Therefore, context matters.

Language: Английский

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Human host defence peptide LL-37 suppresses TNFα-mediated matrix metalloproteinases MMP9 and MMP13, in human bronchial epithelial cells

Journal of Innate Immunity, Journal Year: 2024, Volume and Issue: unknown

Published: March 12, 2024

Introduction: TNFα-inducible matrix metalloproteinases (MMP) play a critical role in the process of airway remodelling respiratory inflammatory disease including asthma. The cationic host defence peptide (CHDP) LL-37 is elevated lungs during inflammation. However, impact on TNFα-driven processes not well understood. Here, we examined effect TNFα-mediated responses human bronchial epithelial cells (HBEC). Methods: We used Slow Off-rate Modified Aptamer-based proteomics approach to define HBEC proteome altered response TNFα. Abundance selected protein candidates and signaling intermediates were using immunoassays, ELISA Western blots, mRNA abundance was by qRT-PCR. Results: Proteomics analysis revealed that 124 proteins significantly altered, 12 enhanced ≥2-fold compared unstimulated cells, MMP9 topmost increased TNFα, ~10-fold MMP13 ~3-fold, cells. Furthermore, demonstrated suppressed HBEC. Mechanistic data production controlled SRC kinase, enhances related upstream negative regulators namely phosphoAKT(T308) TNFAIP3 or A20. Conclusions: findings this study suggest may intervening remodeling chronic such as

Language: Английский

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Unraveling the Intricacies of Neutrophil Extracellular Traps in Inflammatory Bowel Disease: Pathways, Biomarkers, and Promising Therapies

Cytokine & Growth Factor Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

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The Role of Neutrophil Extracellular Traps in Crohn's Disease

Heliyon, Journal Year: 2024, Volume and Issue: 10(23), P. e40577 - e40577

Published: Nov. 20, 2024

Crohn's disease (CD) is an idiopathic and chronic inflammation of the gastrointestinal (GI) tract. The underlying pathogenesis CD multifaceted, with complex interactions between genetic predisposition, environmental triggers, abnormalities within immune system. Neutrophil extracellular traps (NETs) have gained significant attention as a novel component in CD. NETs are intricate structures fashioned from DNA, histones, granule proteins, actively released by neutrophils to entangle eliminate pathogenic microbes. This review article delves into role We examine how may serve pivotal mechanism for recruitment cells site inflammation. known influence function epithelial cells, which line GI tract, potentially contributing structural integrity barrier dysfunction observed stimulate inflammation, hallmark disease, releasing pro-inflammatory molecules activating cells. also investigate promising therapeutic potential targeting By intercepting formation or NETs, it be possible mitigate reduce tissue damage, alleviate symptoms associated Strategies inhibit NET formation, such use DNase I approaches disrupt NET-mediated signaling pathways, discussed therapeutics. Understanding detailed mechanisms crucial development targeted treatments that could revolutionize management

Language: Английский

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The abscopal effect: Implications for drug discovery in autoimmunity

Autoimmunity Reviews, Journal Year: 2023, Volume and Issue: 22(6), P. 103315 - 103315

Published: March 15, 2023

Language: Английский

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Role of LL-37 in Oral Bacterial DNA Accumulation in Dental Plaque

Journal of Dental Research, Journal Year: 2023, Volume and Issue: 103(2), P. 177 - 186

Published: Dec. 13, 2023

Dental plaque, a highly structured polymicrobial biofilm, persistently forms in the oral cavity and is common problem affecting health. The role of defense factors either collaborating or disrupting host-microbiome interactions remains insufficiently elucidated. This study aims to explore LL-37, critical antimicrobial peptide cavity, dental plaque formation. Through immunostaining specimens, we observed that LL-37 DNA colocalized samples, appearing as condensed clusters. In vitro experiments revealed binds rapidly bacterial DNA, forming high molecular weight, DNase-resistant complexes. interaction results losing its inherent antibacterial activity. Further, upon addition visible increase precipitation DNA. We also discovered significant correlation between levels DNA-LL-37 complex within demonstrating ubiquity biofilm. By using on could determine was present clusters small cell-like structures. suggests immediately associates with released form complexes subsequently diffuse. demonstrated exhibited similar Toll-like receptor 9-stimulating activities across different species, including

Language: Английский

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Effects of exogenous deoxyribonuclease I in collagen antibody-induced arthritis

Journal of Inflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Sept. 9, 2024

Language: Английский

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