Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 18, 2024

Abstract Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in COVID-19 vaccines and late-stage clinical studies other indications. However, we others shown that LNPs induce severe inflammation, massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids analyses signaling pathways, elucidate mechanisms LNP-associated inflammation demonstrate solutions. We show LNPs’ hallmark feature, endosomal escape, which is necessary expression, also directly triggers by causing membrane damage. Large, irreparable, holes are recognized cytosolic proteins called galectins, bind to sugars inner then regulate downstream find inhibition galectins abrogates both vitro vivo . rapidly biodegradable ionizable can preferentially create smaller size reparable sorting complex required transport (ESCRT) pathway. Ionizable producing such ESCRT-recruiting produce high expression from cargo mRNA with minimal Finally, routes non-inflammatory LNPs, either galectin or lipids, compatible therapeutic mRNAs ameliorate disease models. without lead exacerbation these In summary, escape induces damage be controlled inhibiting (large hole detectors) ESCRT These strategies should generally safer used treat inflammatory diseases.

Language: Английский

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Ocular neuroinflammatory response secondary to SARS-CoV-2 infection-a review

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 4, 2025

With the consistent occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, prevalence various ocular complications has increased over time. SARS-CoV-2 infection been shown to have neurotropism and therefore lead not only peripheral inflammatory responses but also neuroinflammation. Because receptor for SARS-CoV-2, angiotensin-converting enzyme (ACE2), can be found in many intraocular tissues, disease 2019 (COVID-19) may contribute persistent neuroinflammation, microcirculation dysfunction symptoms. Increased awareness neuroinflammation future research on interventional strategies are important improving long-term outcomes, reducing burden, quality life. Therefore, aim this review is focus discuss current evidence perspectives, especially possible connections between conditions potential treatment strategies.

Language: Английский

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Interplay of Chemokines Receptors, Toll-like Receptors, and Host Immunological Pathways

Biomedicines, Journal Year: 2023, Volume and Issue: 11(9), P. 2384 - 2384

Published: Aug. 25, 2023

A comprehensive framework has been established for understanding immunological pathways, which can be categorized into eradicated and tolerable immune responses. Toll-like receptors (TLRs) are associated with specific TH1 immunity is related to TLR7, TLR8, TLR9, while TH2 TLR1, TLR2, TLR6. TH22 linked TLR4, TLR5, THαβ (Tr1) TLR3, TLR9. The chemokine receptor CXCR5 a marker of follicular helper T cells, other also classified within based on host pathways. On the basis literature review chemokines following associations were identified: CCR5 responses, CCR1 TH1-like CCR4 (basophils) CCR3 (eosinophils) TH9 CCR10 CCR6 TH17 CXCR3 CCR8 regulatory cells (Treg), CCR2 TH3 These findings contribute identification biomarkers provide insights Understanding system crucial comprehending function innate system, as well adaptive

Language: Английский

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A comprehensive approach to developing a multi-epitope vaccine against Mycobacterium tuberculosis: from in silico design to in vitro immunization evaluation

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 2, 2023

Introduction The Bacillus Calmette-Guérin (BCG) vaccine, currently used against tuberculosis (TB), exhibits inconsistent efficacy, highlighting the need for more potent TB vaccines. Materials and methods In this study, we employed reverse vaccinology techniques to develop a promising multi-epitope vaccine (MEV) candidate, called PP13138R, prevention. PP13138R comprises 34 epitopes, including B-cell, cytotoxic T lymphocyte, helper lymphocyte epitopes. Using bioinformatics immunoinformatics tools, assessed physicochemical properties, structural features, immunological characteristics of PP13138R. Results candidate demonstrated excellent antigenicity, immunogenicity, solubility without any signs toxicity or sensitization. silico analyses revealed that interacts strongly with Toll-like receptor 2 4, stimulating innate adaptive immune cells produce abundant antigen-specific antibodies cytokines. vitro experiments further supported efficacy by significantly increasing population IFN-γ + lymphocytes production IFN-γ, TNF-α, IL-6, IL-10 cytokines in active patients, latent infection individuals, healthy controls, revealing compare responses elicited across different stages Mycobacterium infection. Conclusion These findings highlight potential as MEV characterized favorable solubility,

Language: Английский

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Antibodies Specific to Rheumatologic and Neurologic Pathologies Found in Patient with Long COVID

Rheumato, Journal Year: 2025, Volume and Issue: 5(1), P. 1 - 1

Published: Jan. 20, 2025

The SARS-CoV-2 virus can cause hyperstimulation of the immune system, sometimes leading to production various autoantibodies and increased levels interferons interleukins in blood plasma. Background/Objectives: Only a few studies are currently focusing on dynamics immunological indices after any transferred infectious disease encountered by an organism for first time. attention researchers clinicians is captured antibody titers immunologic markers (interferons interleukins), as well correlation with changes symptomatology long COVID. This paper discusses association antibodies against autoantigens rheumatological neurological manifestations COVID-19. Our study patient was 36-year-old man diagnosed polyneuropathy, which developed We conducted dynamic follow-up two years. Methods: plasma samples collected were analyzed ELISA different autoantigens, IFN-γ, variety interleukins. Results: An between rheumatologic neurologic patients COVID symptoms considered. Antibody myelin basic protein (MBP), double-stranded DNA (dsDNA), single-stranded IL-1, IL-6, IL-10 significantly during posthospital period when reported persistent COVID, complaints decreasing resolved. Conclusions: findings this shed light alterations factors, elucidate mechanism infection disrupts immunotolerance eventually restores equilibrium, pathology. Significantly, notable rise transient did not lead progression autoimmune

Language: Английский

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Salvianolic Acid A Attenuates Lipopolysaccharide‐Induced Acute Lung Injury by Activating AMPK/SIRT1/Nrf2 Signaling Pathway

Journal of Biochemical and Molecular Toxicology, Journal Year: 2025, Volume and Issue: 39(5)

Published: April 24, 2025

ABSTRACT Salvianolic acid A (Sal A) has been reported to have anti‐inflammatory and antioxidant properties. The present study aimed explore the potential mechanisms of Sal on lipopolysaccharide (LPS)‐induced acute lung injury (ALI). results indicated that pretreatment attenuated LPS induced injury, shown by alleviated histopathological damage alveolar‐capillary barrier dysfunction, as well reduced inflammatory response oxidative stress. Moreover, effectively increased expression p‐AMPK SIRT1 promoted Nrf2 nuclear translocation in tissues. However, these effects were remarkably blunted Compound C. Molecular docking experiments further confirmed bound active sites AMPK SIRT1. In conclusion, exerted its protective LPS‐induced ALI through suppressing inflammation stress, which was mainly dependent activation AMPK/SIRT1/Nrf2 signaling pathway.

Language: Английский

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Types of cell death and their relations to host immunological pathways

Aging, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 8, 2024

Various immune pathways have been identified in the host, including TH1, TH2, TH3, TH9, TH17, TH22, TH1-like, and THαβ reactions. While TH2 TH9 responses primarily target multicellular parasites, host directed against viruses, intracellular microorganisms (such as bacteria, protozoa, fungi), extracellular can employ programmed cell death mechanisms to initiate or execute effective strategies for pathogen elimination. The types of involved include apoptosis, autophagy, pyroptosis, ferroptosis, necroptosis, NETosis. Specifically, apoptosis is associated with anti-virus eradicable immunity, autophagy tolerable TH3 pyroptosis anti-intracellular microorganism TH1 ferroptosis TH1-like necroptosis anti-extracellular TH22 NETosis TH17 immunity.

Language: Английский

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Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 13, 2024

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which can result in disease, often characterised by a ‘cytokine storm’ and the associated distress syndrome. However, many infections with SARS-CoV-2 are mild or asymptomatic throughout course of infection. Although blood biomarkers disease well studied, less understood inflammatory signatures lung tissues silent infections, wherein infection inflammation rapidly resolved leading to sequelae-free recovery. Herein we described RNA-Seq histological analyses lungs over time an omicron BA.1/K18-hACE2 mouse model, displays these latter features. robust was evident at days post (dpi), viral RNA largely cleared 10 dpi. Acute showed slightly different pattern cytokine compared models, where much diminished 30 dpi absent 66 Cellular deconvolution identified significantly increased abundance scores for number anti-inflammatory pro-resolution cell types 5/10 These included type II innate lymphoid cells, T regulatory interstitial macrophages. Genes whose expression trended downwards – were pathways. upward during this period recovery ciliated AT2 AT1 transition, reticular fibroblasts indicating return homeostasis. Very few differentially expressed host genes dpi, suggesting near complete parallels between subclinical humans those observed model discussed reference concept “protective inflammation”.

Language: Английский

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Progress in cytokine research for ARDS: A comprehensive review

Open Medicine, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 1, 2024

Abstract Introduction Acute respiratory distress syndrome (ARDS) is a critical form of acute failure characterized by diffuse alveolar damage, refractory hypoxemia, and non-cardiogenic pulmonary edema, resulting in high mortality. Dysregulated inflammation, driven cytokines, central to ARDS pathogenesis, progression, prognosis. Objective This review synthesizes current knowledge on the role cytokines evaluates their potential as therapeutic targets, offering new insights for clinical management. Methods A comprehensive analysis recent studies was conducted explore roles pro-inflammatory (e.g., IL-1β, IL-6, IL-8) anti-inflammatory IL-10, IL-22) pathogenesis assess emerging therapies targeting these cytokines. Results Pro-inflammatory are crucial initiating inflammatory responses lung injury early ARDS, while help regulate resolve inflammation. Targeted therapies, such IL-1 IL-6 inhibitors, show managing particularly COVID-19, but efficacy still debated. Combination therapy strategies may enhance outcomes, further large-scale, multicenter randomized controlled trials required establish safety efficacy. Conclusion Understanding cytokine regulation could lead innovative approaches. Future research should focus across subtypes stages develop biomarker-driven, individualized treatments.

Language: Английский

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Nebulized glycyrrhizin/enoxolone drug modulates IL-17A in COVID-19 patients: a randomized clinical trial

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 12, 2024

Glycyrrhizin (GA) and its derivative Enoxolone (18β), isolated from the

Language: Английский

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