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Trabectedin is an antineoplastic drug used to treat soft tissue sarcomas. Trabectedin is mainly infused from the central venous port (CVP) because trabectedin leakage causes serious skin and soft tissue complications. Characteristic sterile inflammation has recently been reported after infusion of trabectedin from the CVP. Here, we report a case of sterile inflammation along a tunneled catheter pathway after trabectedin infusion from the CVP, with residual postinflammatory changes even after CVP removal. A 57-year-old man with myxoid liposarcoma developed skin erythema, swelling, and induration along a tunneled catheter pathway of the CVP after 16 cycles of trabectedin infusion through the CVP. The patient was diagnosed with sterile inflammation because various tests were negative for infection. The CVP was removed because the increasing injection resistance made trabectedin infusion difficult. The catheter firmly adhered to the surrounding tissue during removal. The induration and pigmentation along the catheter persisted for 4 months after CVP removal.
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Sterile inflammation is involved in the lung pathogenesis induced by respirable particles, including micro- and nanoplastics. Their increasing amounts in the ambient and in indoor air pose a risk to human health. In two human cell lines (A549 and THP-1) we assessed the proinflammatory behavior of polystyrene nanoplastics (nPS) and microplastics (mPS) (Ø 0.1 and 1 µm). Reproducing environmental aging, in addition to virgin, the cells were exposed to oxidized nPS/mPS. To study the response of the monocytes to the inflammatory signal transmitted by the A549 through the release of soluble factors (e.g. alarmins and cytokines), THP-1 cells were also exposed to the supernatants of previously nPS/mPS-treated A549. After dynamic-light-scattering (DLS) analysis and protein measurements for the assessment of protein corona in nPS/mPS, real-time PCR and enzyme-linked-immunosorbent (ELISA) assays were performed in exposed cells. The pro-inflammatory effects of v- and ox-nPS/mPS were attested by the imbalance of the Bax/Bcl-2 ratio in A549, which was able to trigger the inflammatory cascade, inhibiting the immunologically silent apoptosis. The involvement of NFkB was confirmed by the overexpression of p65 after exposure to ox-nPS and v- and ox-mPS. The fast and higher levels of IL-1ß, only in THP-1 cells, underlined the NLPR3 inflammasome activation.
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Arteriogenesis is an inflammatory driven mechanism, describing the growth of a natural bypass from pre-existing collateral arteries to compensate for an occluded artery. The complement system component C3 is a potent natural inflammatory activator. Here, we investigated its impact on the process of collateral artery growth using C3-deficient (C3 -/-) and wildtype control mice in a murine hindlimb model of arteriogenesis. Induction of arteriogenesis by unilateral femoral artery ligation resulted in decreased perfusion recovery in C3 -/- mice on day 7 as shown by Laser Doppler imaging. Immunofluorescence staining revealed a reduced vascular cell proliferation in C3 -/- mice. Gene expression analysis displayed a significant reduction in monocyte chemoattractant protein-1 (MCP-1) expression in C3 -/- mice. Interestingly, 3 days after induction of arteriogenesis, the number of macrophages (CD68+) recruited to growing collaterals was not affected by C3 deficiency. However, a significant reduction in inflammatory M1-like polarized macrophages (CD68+/MRC1-) was noted. Forced mast cell activation by Compound 48/80 as well as exogenous MCP-1 application rescued the number of M1-like polarized macrophages along with perfusion recovery in C3 -/- mice. In summary, this study demonstrates that complement C3 influences arteriogenesis by mediating MCP-1 expression, which is essential for the induction and enhancement of sterile inflammation.
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Circulación Colateral , Complemento C3 , Inflamación , Animales , Inflamación/patología , Ratones , Complemento C3/metabolismo , Complemento C3/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Macrófagos/metabolismo , Neovascularización Fisiológica/genética , Ratones Endogámicos C57BL , Miembro Posterior/irrigación sanguínea , Ratones Noqueados , Arteria Femoral/patología , Arterias/crecimiento & desarrollo , Arterias/metabolismo , Masculino , Proliferación Celular , Mastocitos/metabolismoRESUMEN
Liver transplantation remains the only definitive treatment for end-stage liver diseases. However, the increasing prevalence of fatty liver disease among potential donors exacerbates the shortage of suitable organs. This study evaluates the efficacy of the preservation solution Institut Georges Lopez-2 (IGL-2) compared to Histidine-Tryptophan-Ketoglutarate (HTK) and University of Wisconsin (UW) preservation solutions in mitigating ischemia-reperfusion injury (IRI) in steatotic livers. Using Zucker Obese rat livers, we assessed the impact of 24-h static cold storage (SCS) with each solution on transaminase release, glutathione redox balance, antioxidant enzyme activity, lipoperoxidation, and inflammation markers. IGL-2 and UW solutions demonstrated reduced transaminase and lactate levels compared to HTK, indicating better preservation of liver integrity. IGL-2 maintained a higher reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, suggesting more effective management of oxidative stress. Antioxidant enzyme activities catalase, superoxide dismutase, and glutathione peroxidase (CAT, SOD, GPX) were higher in IGL-2 preserved livers, contributing to decreased oxidative damage. Lipid peroxidation markers and inflammatory markers were lower in IGL-2 than in HTK, indicating reduced oxidative stress and inflammation. Additionally, improved mitochondrial function was observed in the IGL-2 group, correlating with reduced reactive oxygen species (ROS) production and lipid peroxidation. These findings suggest that IGL-2 offers superior preservation of liver viability, reduces oxidative stress, and minimizes inflammation compared to HTK and UW solutions. By maintaining a higher ratio of reduced glutathione and antioxidant enzyme activity, IGL-2 effectively mitigates the harmful effects of ischemia-reperfusion injury. The reduced lipid peroxidation and inflammation in the IGL-2 group further underscore its potential in improving liver transplant outcomes. These results highlight the importance of optimizing preservation solutions to enhance the viability and functionality of donor organs, potentially expanding the donor pool and improving the success rates of liver transplantation. Future research should focus on refining preservation techniques and exploring additional protective agents to further improve organ preservation and transplant outcomes.
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Adenosina , Alopurinol , Antioxidantes , Hígado Graso , Insulina , Hígado , Soluciones Preservantes de Órganos , Procaína , Rafinosa , Ratas Zucker , Daño por Reperfusión , Animales , Soluciones Preservantes de Órganos/farmacología , Ratas , Rafinosa/farmacología , Insulina/metabolismo , Adenosina/metabolismo , Adenosina/farmacología , Hígado Graso/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/patología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Antioxidantes/farmacología , Antioxidantes/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Alopurinol/farmacología , Masculino , Procaína/farmacología , Inflamación/metabolismo , Inflamación/patología , Inflamación/tratamiento farmacológico , Glucosa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Manitol/farmacología , Isquemia Fría/efectos adversos , Cloruro de Potasio/farmacología , Preservación de Órganos/métodos , Trasplante de Hígado/métodosRESUMEN
Stimulator of interferon genes (STING) has recently been found to play a crucial role in cardiac sterile inflammation and dysfunction. The role of stimulator of interferon genes (STING) in cardiac sterile inflammation and dysfunction has been recently discovered. This study aims to examine the involvement of STING in pathological cardiac remodeling and the mechanisms that govern the activation of the STING pathway. To investigate this, transverse aortic constriction (TAC) was performed on STING knockout mice to induce pressure overload-induced cardiac remodeling. Subsequently, cardiac function, remodeling, and inflammation levels were evaluated. The STING pathway was found to be activated in the pressure overload-stressed heart and angiotensin II (Ang II)-stimulated cardiac fibroblasts. Loss of STING expression led to a significant reduction in inflammatory responses, mitochondrial fragmentation, and oxidative stress in the heart, resulting in attenuated cardiac remodeling and dysfunction. Furthermore, the exacerbation of pressure overload-induced STING-mediated inflammation and pathological cardiac remodeling was observed when mitophagy was suppressed through the silencing of Parkin, an E3 ubiquitin ligase. Taken together, these findings indicate that STING represents a newly identified and significant molecule implicated in the process of pathological cardiac remodeling and that mitophagy is an upstream mechanism that regulates STING activation. Targeting STING may therefore provide a novel therapeutic strategy for pathological cardiac remodeling and heart failure.
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Sterile inflammation occurs in various chronic diseases due to many nonmicrobe factors. Examples include endometrial hyperplasia (EH), endometriosis, endometrial cancer, and breast cancer, which are all sterile inflammation diseases induced by estrogen imbalances. However, how estrogen-induced sterile inflammation regulates EH remains unclear. Here, a single-cell RNA-Seq is used to show that SHP2 upregulation in endometrial endothelial cells promotes their inflammatory activation and subsequent transendothelial macrophage migration. Independent of the initial estrogen stimulation, IL1ß and TNFα from macrophages then create a feedforward loop that enhances endothelial cell activation and IGF1 secretion. This endothelial cell-macrophage interaction sustains sterile endometrial inflammation and facilitates epithelial cell proliferation, even after estradiol withdrawal. The bulk RNA-Seq results and phosphoproteomic analysis show that endothelial SHP2 mechanistically enhances RIPK1 activity by dephosphorylating RIPK1Tyr380. This event activates downstream activator protein 1 (AP-1) and instigates the inflammation response. Furthermore, targeting SHP2 using SHP099 (an allosteric inhibitor) or endothelial-specific SHP2 deletion alleviates endothelial cell activation, macrophage infiltration, and EH progression in mice. Collectively, the findings demonstrate that SHP2 mediates the transition of endothelial activation from estradiol-driven acute inflammation to macrophage-amplified chronic inflammation. Targeting sterile inflammation mediated by endothelial cell activation is a promising strategy for nonhormonal intervention in estrogen-related diseases.
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The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is one of the fundamental mechanisms of the body's defense, which responds to the abnormal presence of double-stranded DNA in the cytoplasm to establish an effective natural immune response. In addition to detecting microbial infections, the cGAS pathway may be triggered by any cytoplasmic DNA, which is absent from the normal cytoplasm, and only conditions such as senescence and mitochondrial stress can lead to its leakage and cause sterile inflammation. A growing body of research has shown that the cGAS-STING pathway is strongly associated with sterile inflammation. In this study, we reviewed the regulatory mechanisms and biological functions of the cGAS-STING pathway through its involvement in aseptic inflammation in liver disease, kidney disease, and cellular senescence.
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Senescencia Celular , Enfermedades Renales , Hepatopatías , Proteínas de la Membrana , Nucleotidiltransferasas , Transducción de Señal , Humanos , Nucleotidiltransferasas/metabolismo , Senescencia Celular/inmunología , Proteínas de la Membrana/metabolismo , Enfermedades Renales/inmunología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Animales , Hepatopatías/inmunología , Hepatopatías/metabolismoRESUMEN
Beta glucans are found in many natural sources, however, only Baker's Yeast Beta Glucan (BYBG) has been well documented to have structure-function effects that are associated with improved innate immune response to stressors (e.g., exercise, infection, etc.). The purpose was to identify a BYBG-associated mRNA expression pattern following exercise. Participants gave IRB-approved consent and were randomized to BYBG (Wellmune®; N=9) or Placebo (maltodextrin; N=10) for 6-weeks prior to performing 90 min of whole-body exercise. Paxgene blood samples were collected prior to exercise (PRE), after exercise (POST), two hours after exercise (2H), and four hours after exercise (4H). Total RNA was isolated and analyzed for the expression of 770 innate immune response mRNA (730 mRNA targets; 40 housekeepers/controls; Nanostring nCounter). The raw data were normalized against housekeeping controls and expressed as Log2 fold change from PRE for a given condition. Significance was set at p < 0.05 with adjustments for multiple comparisons and false discovery rate. We identified 47 mRNA whose expression was changed after exercise with BYBG and classified them to four functional pathways: 1) Immune Cell Maturation (8 mRNA), 2) Immune Response and Function (5 mRNA), 3) Pattern Recognition Receptors and DAMP or PAMP Detection (25 mRNA), and 4) Detection and Resolution of Tissue Damage (9 mRNA). The identified mRNA whose expression was altered after exercise with BYBG may represent an innate immune response pattern and supports previous conclusions that BYBG improves immune response to a future sterile inflammation or infection.
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Ejercicio Físico , Inmunidad Innata , ARN Mensajero , Saccharomyces cerevisiae , beta-Glucanos , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/genética , beta-Glucanos/farmacología , beta-Glucanos/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ejercicio Físico/fisiología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/inmunología , Masculino , Suplementos Dietéticos , Adulto , Femenino , Adulto Joven , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
Background: The periodontal ligament (PDL) experiences considerable mechanical stresses between teeth and bone, vital for tissue adaptation, especially in orthodontic tooth movement (OTM). While recent research emphasizes the role of innate lymphoid cells (ILCs) in regulating sterile inflammation, their involvement in periodontal tissues during OTM remains largely unexplored. Methods: In this study, PDL tissues from orthodontic patients (n = 8) were examined using flow cytometry to detect ILC subtypes. Transwell co-culture systems were used to expose PDL cells to mechanical strain, followed by measuring migration and ratios of sorted ILC subtypes. Statistical analyses were conducted using paired Student's t-test, Kruskal-Wallis test, Dunn's post-test and one-way/two-way ANOVA with Tukey's post-test (p≤ 0.05; **, p≤ 0.01; ***, p≤ 0.001). Results: Our findings demonstrate a significant increase in CD127+ CD161+ ILC frequencies in PDL tissues during OTM, indicating ILC involvement in sterile inflammation induced by orthodontic forces. Co-culture assays show directed migration of ILC subsets towards PDL cells and substantial proliferation and expansion of ILCs. Conclusions: This study is the first to comprehensively investigate the role of ILCs in sterile inflammation during OTM, revealing their presence and distribution within PDL tissues' innate immune response in vivo, and exploring their migratory and proliferative behavior in vitro. The results suggest a crosstalk between ILCs and PDL cells, potentially influencing the inflammatory response and tissue remodeling processes associated with OTM.
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Inmunidad Innata , Linfocitos , Ligamento Periodontal , Técnicas de Movimiento Dental , Humanos , Linfocitos/inmunología , Femenino , Masculino , Ligamento Periodontal/inmunología , Ligamento Periodontal/citología , Adolescente , Técnicas de Cocultivo , Periodoncio/inmunología , Adulto Joven , Células Cultivadas , Adulto , Movimiento Celular/inmunologíaRESUMEN
The prevalence of age-related neurodegenerative diseases, such as Parkinson's disease (PD) and related disorders continues to grow worldwide. Increasing evidence links intracellular inclusions of misfolded alpha-synuclein (α-syn) aggregates, so-called Lewy bodies (LB) and Lewy neuritis, to the progressive pathology of PD and other synucleinopathies. Our previous findings established that α-syn oligomers induce S-nitrosylation and deregulation of the E3-ubiquitin ligase Parkin, leading to mitochondrial disturbances in neuronal cells. The accumulation of damaged mitochondria as a consequence, together with the release of mitochondrial-derived damage-associated molecular patterns (mtDAMPs) could activate the innate immune response and induce neuroinflammation ("mito-inflammation"), eventually accelerating neurodegeneration. However, the molecular pathways that transmit pro-inflammatory signals from damaged mitochondria are not well understood. One of the proposed pathways could be the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) (cGAS-STING) pathway, which plays a pivotal role in modulating the innate immune response. It has recently been suggested that cGAS-STING deregulation may contribute to the development of various pathological conditions. Especially, its excessive engagement may lead to neuroinflammation and appear to be essential for the development of neurodegenerative brain diseases, including PD. However, the precise molecular mechanisms underlying cGAS-STING pathway activation in PD and other synucleinopathies are not fully understood. This review focuses on linking mitochondrial dysfunction to neuroinflammation in these disorders, particularly emphasizing the role of the cGAS-STING signaling. We propose the cGAS-STING pathway as a critical driver of inflammation in α-syn-dependent neurodegeneration and hypothesize that cGAS-STING-driven "mito-inflammation" may be one of the key mechanisms promoting the neurodegeneration in PD. Understanding the molecular mechanisms of α-syn-induced cGAS-STING-associated "mito-inflammation" in PD and related synucleinopathies may contribute to the identification of new targets for the treatment of these disorders.
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Podermatitis aseptica hemorrhagica circumscripta is associated with metalloproteinase 2 weakening of distal phalangeal suspensory structures and sinkage of the distal phalanx in the claw capsule. Pressure from the tuberculum flexorium on the sole epidermis and dermis produces hemorrhagic tissue injury and defective horn production appearing as yellow-red, softened claw horn in region 4 of the sole. A model of the MAPK/ERK signal cascade orchestrating epidermal-dermal homeostasis was employed to determine if sterile inflammatory responses are linked to disturbed signal transduction for epidermal homeostasis in sole epidermis and dermis. The objective was to assess shifts in target genes of inflammation, up- and downstream MAPK/ERK signal elements, and targeted genes supporting epidermal proliferation and differentiation. Sole epidermis and dermis was removed from lateral claws bearing lesions of podermatitis aseptica hemorrhagica circumscripta, medial claws from the same limb and lateral claws from completely normal limbs of multiparous, lactating Holstein cows. The abundance levels of targeted transcripts were evaluated by real-time QPCR. Lesion effects were assessed by ANOVA, and mean comparisons were performed with t-tests to assess variations between mean expression in ulcer-bearing or medial claw dermis and epidermis and completely normal lateral claw dermis and epidermis or between ulcer-bearing dermis and epidermis and medial claw dermis and epidermis. The lesions were sterile and showed losses across multiple growth factors, their receptors, several downstream AP1 transcription components, CMYC, multiple cell cycle and terminal differentiation elements conducted by MAPK/ERK signals and ß 4, α 6 and collagen 17A hemidesmosome components. These losses coincided with increased cytokeratin 6, ß 1 integrin, proinflammatory metalloproteinases 2 and 9, IL1B and physiologic inhibitors of IL1B, the decoy receptor and receptor antagonist. Medial claw epidermis and dermis from limbs with lateral claws bearing podermatitis aseptica hemorrhagica circumscripta showed reductions in upstream MAPK/ERK signal elements and downstream targets that paralleled those in hemorrhagic lesions. Inhibitors of IL1B increased in the absence of real increases in inflammatory targets in the medial claw dermis and epidermis. Losses across multiple signal path elements and downstream targets were associated with negative effects on targeted transcripts supporting claw horn production and wound repair across lesion-bearing lateral claws and lesion-free medial claw dermis and epidermis. It was unclear if the sterile inflammation was causative or a consequence of these perturbations.
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Purpose Sterile inflammation along the tunneled catheter is a characteristic complication associated with trabectedin infusion via a central venous port (CVP). To date, no studies have evaluated the differences in sterile inflammation incidence according to the CVP system used. This study evaluated the differences in sterile inflammation incidence between two different CVP systems. Methods This study was conducted at The University of Tokyo Hospital, Bunkyo-Ku, Tokyo, Japan. Patients with trabectedin infusion using CVP via the internal jugular vein between April 2016 and February 2024 were retrospectively evaluated. Sterile inflammation was characterized as skin erythema, swelling, pain, or induration along the tunneled catheter after infusion of trabectedin from the CVP and negative for various infection tests. The incidence of sterile inflammation was compared using two different CVP systems: Anthron® polyurethane catheter with Celsite port (P-U Celsite; Toray Medical, Tokyo, Japan) and DewX Eterna (Terumo, Tokyo, Japan). Results Of the 21 patients, 12 and nine patients used P-U Celsite and DewX Eterna for trabectedin infusion, respectively. Sterile inflammation occurred in five patients; of these, four underwent CVP removal because of worsened pain, making trabectedin infusion difficult. Sterile inflammation occurred in 0 (0/12) and 56% (5/9) of patients using P-U Celsite and DewX Eterna, respectively, with a significantly lower incidence in patients using P-U Celsite (P = 0.006). Conclusion Sterile inflammation incidence was significantly lower in patients using P-U Celsite compared to those using DewX Eterna.
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Fever during childbirth, which is often observed in clinical settings, is characterized by a temperature of 38°C or higher, and can occur due to infectious and non-infectious causes. A significant proportion of non-infectious causes are associated with epidural-related maternal fever during vaginal delivery. Therapeutic interventions are required because fever has adverse effects on both mother and newborn. Effective treatment options for ERMF are lacking. As it is difficult to distinguish it from intrauterine infections such as chorioamnionitis, antibiotic administration remains the only viable option. We mentioned the importance of interleukin-1 receptor antagonist in the sterile inflammatory fever pathway and the hormonal influence on temperature regulation during childbirth, an important factor in elucidating the pathophysiology of ERMF. This review spotlighted the etiology and management of ERMF, underscoring recent advancements in our understanding of hypothalamic involvement in thermoregulation and its link to sterile inflammation. We propose to deepen the understanding of ERMF within the broader context of autonomic neuroscience, aiming to foster the development of targeted therapies.
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Peritoneal dialysis is a widely used method for treating kidney failure. However, over time, the peritoneal structure and function can deteriorate, leading to the failure of this therapy. This deterioration is primarily caused by infectious and sterile inflammation. Sterile inflammation, which is inflammation without infection, is particularly concerning as it can be subtle and often goes unnoticed. The onset of sterile inflammation involves various pathological processes. Peritoneal cells detect signals that promote inflammation and release substances that attract immune cells from the bloodstream. These immune cells contribute to the initiation and escalation of the inflammatory response. The existing literature extensively covers the involvement of different cell types in the sterile inflammation, including mesothelial cells, fibroblasts, endothelial cells, and adipocytes, as well as immune cells such as macrophages, lymphocytes, and mast cells. These cells work together to promote the occurrence and progression of sterile inflammation, although the exact mechanisms are not fully understood. This review aims to provide a comprehensive overview of the signals from both stromal cells and components of immune system, as well as the reciprocal interactions between cellular components, during the initiation of sterile inflammation. By understanding the cellular and molecular mechanisms underlying sterile inflammation, we may potentially develop therapeutic interventions to counteract peritoneal membrane damage and restore normal function.
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Comunicación Celular , Diálisis Peritoneal , Peritoneo , Células del Estroma , Humanos , Diálisis Peritoneal/efectos adversos , Peritoneo/patología , Peritoneo/inmunología , Animales , Células del Estroma/inmunología , Comunicación Celular/inmunología , Inflamación/inmunología , Peritonitis/inmunologíaRESUMEN
The field of nephrology has recently directed a considerable amount of attention towards the stimulator of interferon genes (STING) molecule since it appears to be a potent driver of chronic kidney disease (CKD). STING and its activator, the cyclic GMP-AMP synthase (cGAS), along with intracellular RIG-like receptors (RLRs) and toll-like receptors (TLRs), are potent inducers of type I interferon (IFN-I) expression. These cytokines have been long recognized as part of the mechanism used by the innate immune system to battle viral infections; however, their involvement in sterile inflammation remains unclear. Mounting evidence pointing to the involvement of the IFN-I pathway in sterile kidney inflammation provides potential insights into the complex interplay between the innate immune system and damage to the most sensitive segment of the nephron, the glomerulus. The STING pathway is often cited as one cause of renal disease not attributed to viral infections. Instead, this pathway can recognize and signal in response to host-derived nucleic acids, which are also recognized by RLRs and TLRs. It is still unclear, however, whether the development of renal diseases depends on subsequent IFN-I induction or other processes involved. This review aims to explore the main endogenous inducers of IFN-I in glomerular cells, to discuss what effects autocrine and paracrine signaling have on IFN-I induction, and to identify the pathways that are implicated in the development of glomerular damage.
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Interferón Tipo I , Virosis , Humanos , Inmunidad Innata , Transducción de Señal/fisiología , Cicatriz , Interferón Tipo I/metabolismo , Receptores Toll-Like , InflamaciónRESUMEN
Z-DNA binding protein 1 (ZBP1), a cytosolic nucleic acid sensor for Z-form nucleic acids (Z-NA), can detect both exogenous and endogenous nucleic acids. Upon sensing of self Z-NA or exposure to diverse noxious stimuli, ZBP1 regulates inflammation by activating nuclear factor kappa B and interferon regulating factor 3 signaling pathways. In addition, ZBP1 promotes the assembly of ZBP1 PANoptosome, which initiates caspase 3-mediated apoptosis, mixed lineage kinase domain like pseudokinase (MLKL)-mediated necroptosis, and gasdermin D (GSDMD)-mediated pyroptosis (PANoptosis), leading to the release of various damage-associated molecular patterns. Thereby, ZBP1 is implicated in the development and progression of diverse sterile inflammatory diseases. This review outlines the expression, structure, and function of ZBP1, along with its dual roles in controlling inflammation and cell death to orchestrate innate immunity in sterile inflammation, especially autoimmune diseases, and cancers. ZBP1 has emerged as an attractive therapeutic target for various sterile inflammatory diseases.
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Ácidos Nucleicos , Humanos , Apoptosis , Muerte Celular , Piroptosis , Inflamación/genéticaRESUMEN
Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis.
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Ácido Láctico , Psoriasis , Ratones , Animales , Ácido Láctico/metabolismo , Ácido Láctico/farmacología , Piel/metabolismo , Macrófagos/metabolismo , Inflamación/metabolismo , Psoriasis/metabolismoRESUMEN
Acetaminophen overdose is a leading cause of acute liver failure (ALF). Despite the pivotal role of the inflammatory microenvironment in the progression of advanced acetaminophen-induced liver injury (AILI), a comprehensive understanding of the underlying cellular interactions and molecular mechanisms remains elusive. Mas is a G protein-coupled receptor highly expressed by myeloid cells; however, its role in the AILI microenvironment remains to be elucidated. A multidimensional approach, including single-cell RNA sequencing, spatial transcriptomics, and hour-long intravital imaging, is employed to characterize the microenvironment in Mas1 deficient mice at the systemic and cell-specific levels. The characteristic landscape of mouse AILI models involves reciprocal cellular communication among MYC+CD63+ endothelial cells, MMP12+ macrophages, and monocytes, which is maintained by enhanced glycolysis and the NF-κB/TNF-α signaling pathway due to myeloid-Mas deficiency. Importantly, the pathogenic microenvironment is delineated in samples obtained from patients with ALF, demonstrating its clinical relevance. In summary, these findings greatly enhance the understanding of the microenvironment in advanced AILI and offer potential avenues for patient stratification and identification of novel therapeutic targets.
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Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Modelos Animales de Enfermedad , Células Endoteliales , Macrófagos , Metaloproteinasa 12 de la Matriz , Monocitos , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Acetaminofén/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Células Endoteliales/metabolismo , Macrófagos/metabolismo , Metaloproteinasa 12 de la Matriz/metabolismo , Metaloproteinasa 12 de la Matriz/genética , Ratones Endogámicos C57BL , Monocitos/metabolismoRESUMEN
Sterile inflammation is a natural response of the organism in the absence of microorganisms, which is triggered in correspondence with the degree of tissue damage sustained after a surgical procedure. The objective of this study was to explore the values of postoperative hematological-derived biomarkers in assessing the sterile inflammatory response magnitude related to the invasiveness of the surgical reduction technique used for subtrochanteric fractures (STFs) treatment. A retrospective, observational cohort research was conducted between January 2021 and October 2023 that included a total of 143 patients diagnosed with acute subtrochanteric fractures who underwent long Gamma Nail (LGN) fixation. According to the surgical reduction technique used, they were divided into two groups: group 1, which consisted of those with a closed reduction and internal fixation (CRIF); and group 2, which consisted of those with an open reduction internal fixation (ORIF). Between groups, statistically significant differences (p < 0.05) were found in relation to days to surgery, length of hospital stay (LOHS), duration of surgery, postoperative hemoglobin (HGB) levels, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), systemic inflammation index (SII), systemic inflammation response index (SIRI), and aggregate inflammation systemic index (AISI). The receiver operating characteristics (ROC) curve analysis revealed that all ratios presented a high diagnostic ability (p < 0.0001) with NLR > 6.95 being the most reliable (sensitivity 94.8% and specificity 70.6%). Moreover, the multivariate regression model confirmed that sterile immune response after orthopedic interventions can be assessed in an almost equal and non-dependent manner using these biomarkers. Postoperative NLR, PLR, MLR, SII, SIRI, and AISI ratios are closely correlated to the sterile inflammatory response magnitude, due to the extent of surgical dissection performed during internal fixation procedures of subtrochanteric femur fractures.
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BACKGROUND: Liver ischemia reperfusion (IR) injury is a common cause of liver dysfunction in patients post liver partial resection and liver transplantation. However, the cellular defense mechanisms underlying IR are not well understood. Macrophage mediated sterile inflammation plays critical roles in liver IR injury. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting. This study aimed to explore the role of sorting nexin 10 (SNX10) during liver IR injury with a focus on regulating macrophage function. METHODS: Both the gene and protein expression levels of SNX10 were analyzed in human specimens from 10 patients undergoing liver partial resection with ischemic insult and in a mouse model of liver IR. The in vivo effects of SNX10 in liver IR injury and sterile inflammation in mice were investigated. Bone marrow derived macrophages (BMDMs) were used to determine the role of SNX10 in modulating macrophage function in vitro. RESULTS: Increased expression of SNX10 was observed both in human specimens and mice livers post IR. SNX10 knockdown alleviated IR induced sterile inflammation and liver damage in mice. SNX10 promoted M1 polarization of macrophage treated with LPS and facilitated inflammatory response by activating NLRP3 inflammasome. CONCLUSIONS: We report for the first time that SNX10 is upregulated in IR-stressed livers. SNX10 activation aggravates liver IR injury and sterile inflammation by facilitating macrophage M1 polarization and inflammatory response suggesting SNX10 as a potential therapeutic target for liver IR injury.