Li Y-, Geng WL, Li CC
… +3 more, Wu JH, Gao F, Wang Y
J Inflamm (Lond)
· 2024 Dec · PMID 39731176
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The chemokine CCL20, a small cytokine that belongs to the C-C chemokine family, interacts with its homologous receptor CCR6, which is expressed on wide range of cell types. According to current research, the CCL20-CCR6 h...The chemokine CCL20, a small cytokine that belongs to the C-C chemokine family, interacts with its homologous receptor CCR6, which is expressed on wide range of cell types. According to current research, the CCL20-CCR6 has been established as acritical player in a diverse range of inflammatory, oncogenic, and autoimmune diseases. Within the respiratory system, CCL20-CCR6 demonstrates heightened expression in conditions such as allergic asthma, chronic airway inflammation, non-small cell lung cancer (NSCLC), chronic obstructive pulmonary disease (COPD), and other respiratory diseases, which is conducive to the inflammatory mediators recruitment and tumor microenvironment remodeling. Numerous studies have demonstrated that therapeutic interventions targeting CCL20 and CCR6, including antibodies and antagonists, have the potential to mitigate disease progression. Despite the promising research prospects surrounding the CCL20-CCR6 chemokine axis, the precise mechanisms underlying its action in respiratory diseases remain largely elusive. In this review, we delve into the potential roles of the CCL20-CCR6 axis within the respiratory system by synthesizing and analyzing current research findings. Our objective is to provide a comprehensive understanding of the CCL20-CCR6 axis and its implications for respiratory health and disease. And we aspire to propel research endeavors in this domain and furnish valuable insights for the development of future therapeutic strategies.
J Inflamm (Lond)
· 2024 Dec · PMID 39707430
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Basement membranes form part of the extracellular matrix (ECM), which is the structural basis for all tissue. Basement membranes are cell-adherent sheets found between cells and vascular endothelia, including those of th...Basement membranes form part of the extracellular matrix (ECM), which is the structural basis for all tissue. Basement membranes are cell-adherent sheets found between cells and vascular endothelia, including those of the central nervous system (CNS). There is exceptional regional specialisation of these structures, both in tissue organisation and regulation of tissue-specific cellular processes. Due to their location, basement membranes perform a key role in immune cell trafficking and therefore are important in inflammatory processes causing or resulting from CNS disease and injury. This review will describe basement membranes in detail, with special focus on the brain. We will cover how genetic changes drive brain pathology, describe basement membranes' role in immune cell recruitment and how they respond to various brain diseases. Understanding how basement membranes form the junction between the immune and central nervous systems will be a major advance in understanding brain disease.
Jamialahmadi T, Reiner Ž, Simental-Mendia LE
… +5 more, Almahmeed W, Karav S, Eid AH, Giammarile F, Sahebkar A
J Inflamm (Lond)
· 2024 Dec · PMID 39696570
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BACKGROUND: Pathogenesis of atherosclerosis is largely mediated by inflammatory process. Statins are lipid-lowering drugs which also have anti-inflammatory effects. 18 fluorine radiolabeled fluorodeoxyglucose (18 F-FDG)...BACKGROUND: Pathogenesis of atherosclerosis is largely mediated by inflammatory process. Statins are lipid-lowering drugs which also have anti-inflammatory effects. 18 fluorine radiolabeled fluorodeoxyglucose (18 F-FDG) positron emission tomography-computed tomography (PET-CT) is considered to be a good indicator of arterial wall inflammation. Therefore, in this meta-analysis the role of statins on inflammatory process in the artery wall was evaluated using this method since its actual validity for this purpose is not yet well established. METHODS: PubMed, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar databases were searched using MESH terms and keywords. Funnel plot, Begg's rank correlation, and Egger's weighted regression tests evaluated publication bias in the meta-analysis. In cases where funnel plot asymmetry was observed, the "trim and fill" method was used to check the input of potentially missing studies. RESULTS: Findings of 10 clinical trials involving 373 subjects showed a remarkable reduction of arterial wall 18 F-FDG uptake according to target-to-background ratio (TBR) index after treatment with statins. Subgroup analysis showed a significant decrease in TBR with high-intensity and non-significant reduction of TBR with low-to-moderate-intensity statin therapy. CONCLUSION: Treatment with statins suppressed arterial wall inflammation as shown by using 18 F-FDG PET-CT.
Gholamalizadeh H, Ensan B, Karav S
… +2 more, Jamialahmadi T, Sahebkar A
J Inflamm (Lond)
· 2024 Dec · PMID 39696507
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BACKGROUND: HMG-CoA reductase inhibitors are well-known medications in the treatment of cardiovascular disorders due to their pleiotropic and lipid-lowering properties. Herein, we reviewed the effects of statins on the C...BACKGROUND: HMG-CoA reductase inhibitors are well-known medications in the treatment of cardiovascular disorders due to their pleiotropic and lipid-lowering properties. Herein, we reviewed the effects of statins on the CCL2/CCR2 axis. METHOD: Scopus and Pubmed databases were systematically searched using the following keywords:" Hydroxymethylglutaryl CoA Reductase Inhibitors"," HMG-CoA Reductase Inhibitors"," Statins", "CCL2, Chemokine", "Monocyte Chemoattractant Protein-1" and "Chemokine (C-C Motif) Ligand 2". Evidence investigating the role of statin on MCP-1 in CVD was identified and bibliographies were completely evaluated to gather further related studies. RESULTS: The anti-inflammatory effects of statins on the CCL2/CCR2 pathway have been widely investigated. Despite inconclusive results, a great body of research supports the regulatory roles of statins on this pathway due to their pleiotropic effects. By disrupting the CCL2/CCR2 axis, statins attenuate the infiltration of monocytes and macrophages into the zone of inflammation and hence down-regulate the inflammatory cascades in various CVDs including atherosclerosis, cardiac remodeling, and stroke, among others. CONCLUSION: CCL2 plays a major role in the pathogenesis of cardiovascular disorders. Down-regulation of CCL2 is proposed as one of the pleiotropic properties of statins. However, more investigations are required to elucidate which statin in what dose exerts a more potent effect on CCL2/CCR2 pathway.
Lu CH, Shen CY, Li KJ
… +5 more, Wu CH, Chen YH, Kuo YM, Hsieh SC, Yu CL
J Inflamm (Lond)
· 2024 Nov · PMID 39605016
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BACKGROUND: Polymorphonuclear neutrophils (PMN) activation by monosodium urate crystals (MSU) is crucial to acute gouty arthritis and subsequent spontaneous remission within 7-10 days. Activated PMNs release neutrophil e...BACKGROUND: Polymorphonuclear neutrophils (PMN) activation by monosodium urate crystals (MSU) is crucial to acute gouty arthritis and subsequent spontaneous remission within 7-10 days. Activated PMNs release neutrophil extracellular traps (NETs) that entrap MSU crystals, forming NET-MSU aggregates. Whether NET-MSU aggregates contribute to the resolution of acute inflammation remains to be elucidated. This study uses a cell-based approach to unveil their molecular bases. METHODS: All-trans retinoic acid-differentiated HL-60 cells (dHL-60) served as surrogate PMNs. NET release from MSU-activated dHL-60 was confirmed by detecting DNA, neutrophil elastase, and citrullinated histone 3, forming large NET-MSU aggregates. NET area was measured with Fiji software after SYTOX Green staining. Released pro-inflammatory cytokines IL-8 and TNF-α, and the anti-inflammatory cytokine IL-1RA in culture supernatants were quantified to calculate the estimate inflammation score (EIS). Cellular redox state was determined by a FRET-based sensor. Expression of intracellular positive (ERK1/2) and negative (SHP-1 and SHIP-1) cytokine signaling regulators was detected by western blot. qPCR detected mRNA expressions of CISH and SOCS1-SOCS7. Flow cytometry measured neutrophil N1 (CD54) and N2 (CD182) surface markers after staining with fluorescent-conjugated antibodies. RESULTS: Incubating dHL-60 with MSU for 4 h maximized NET-MSU aggregate formation and acute inflammation with an EIS of 11.6. Prolonging the incubation of dHL-60 + MSU to 22 h gradually raised the EIS to 19.40 without increasing NET area, due to reduced cellular redox capacity. Adding both new dHL-60 and new MSU crystals to the culture, mimicking the clinical scenario, increased NET area but conversely suppressed EIS to 1.53, indicating acute inflammation resolution. The resolution of acute inflammation following prolonged incubation was attributed to decreases in P-ERK and increases in P-SHP-1, SOCS2, SOCS3, and CISH gene expressions, which may suppress pro-inflammatory and enhance anti-inflammatory cytokine production. Moreover, the large NET-MSU aggregates facilitated N1 to N2 polarization, crucial for accelerating inflammation resolution. CONCLUSION: We explored the potential molecular basis for the spontaneous resolution of MSU induced acute inflammation using a cell-based model in that huge NET-MSU aggregates frustrate the transformation of newly entering PMNs to the N2 phenotype, enhancing the production of the anti-inflammatory cytokine IL-1RA.
J Inflamm (Lond)
· 2024 Nov · PMID 39593038
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Idiopathic inflammatory myopathies are a group of systemic autoimmune diseases characterized by chronic muscle inflammation and diverse clinical manifestations. Macrophages, pivotal components of innate immunity, are imp...Idiopathic inflammatory myopathies are a group of systemic autoimmune diseases characterized by chronic muscle inflammation and diverse clinical manifestations. Macrophages, pivotal components of innate immunity, are implicated in immune responses, inflammation resolution, and tissue repair. Distinct macrophage polarization states play vital roles in disease progression and resolution. Mechanistically, activated macrophages release proinflammatory cytokines, chemokines, and reactive oxygen species, perpetuating immune responses and tissue damage. Dysregulated macrophage polarization contributes to sustained inflammation. Here, we reviewed the intricate contributions of macrophages to IIM pathogenesis and explored novel therapeutic avenues. We discussed emerging strategies targeting macrophages, including receptor-based interventions and macrophage polarization modulation, for IIM treatment. This review underscores the multifaceted involvement of macrophages in IIM pathogenesis and offers insights into potential therapeutic approaches targeting these immune cells for disease management.
McGahon J, Woods S, D'Elia R
… +1 more, Roberts CW
J Inflamm (Lond)
· 2024 Nov · PMID 39593021
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Inflammation can be an unwanted consequence or cause of debilitating diseases of infectious and non-infectious aetiologies. Current anti-inflammatory medications have several deficiencies including lack of specificity an...Inflammation can be an unwanted consequence or cause of debilitating diseases of infectious and non-infectious aetiologies. Current anti-inflammatory medications have several deficiencies including lack of specificity and undesirable side effects. Herein, the potential of non-ionic surfactant vesicles (NISV) comprised of monopalmityol glycerol, dicetyl phosphate and cholesterol) as an anti-inflammatory drug and their mode of action is investigated. NISV were able to inhibit LPS-induced IL-6 from BMD macrophages. The individual components of NISV, monopalmityol glycerol, dicetyl phosphate and cholesterol did not affect LPS induced IL-6 levels, proving that formulation of NISV is essential for their anti-inflammatory effects. Transcriptomic analyses showed NISV mediated down-regulation of transcripts for inflammatory mediators in LPS stimulated macrophages. Notably, NISV downregulate NF-κB transcripts in LPS stimulated macrophages. Measurement of inflammatory mediators by cytometric bead array validated a number of transcriptomic findings as NISV were found to inhibit LPS induced IL-6, IL-12, and multiple chemokines. Further investigation demonstrated that NISV inhibited Poly(I:C) or Pam3csk4 induced inflammatory mediators. This indicates that the effects of NISV are distal to both MyD88 and TRIF signalling. Overall, the data generated highlights the potential of NISV as an anti-inflammatory therapeutic.
Xu L, Yang X, Liu XT
… +6 more, Li XY, Zhu HZ, Xie YH, Wang SW, Li Y, Zhao Y
J Inflamm (Lond)
· 2024 Nov · PMID 39548566
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BACKGROUND: Sepsis-induced myocardial dysfunction (SIMD) may contribute to the poor prognosis of septic patients. Carvacrol (2-methyl-5-isopropyl phenol), a phenolic monoterpene compound extracted from various aromatic p...BACKGROUND: Sepsis-induced myocardial dysfunction (SIMD) may contribute to the poor prognosis of septic patients. Carvacrol (2-methyl-5-isopropyl phenol), a phenolic monoterpene compound extracted from various aromatic plants and fragrance essential oils, has multiple beneficial effects such as antibacterial, anti-inflammatory, and antioxidant properties. These attributes make it potentially useful for treating many diseases. This study aims to investigate the effects of CAR on LPS-induced myocardial dysfunction and explore the underlying mechanism. RESULTS: H9c2 cells were stimulated with 10 µg/ml LPS for 12 h, and c57BL/6 mice were intraperitoneally injected with 10 mg/kg LPS to establish a septic-myocardial injury model. Our results showed that CAR could improve cardiac function, significantly reduce serum levels of inflammatory cytokines (including TNF-α, IL-1β, and IL-6), decrease oxidative stress, and inhibit cardiomyocyte apoptosis in LPS-injured mice. Additionally, CAR significantly downregulated the expression of TLR4, MyD88, and NF-κB in LPS-injured mice and H9c2 cells. It also inhibited the upregulation of inflammasome components (such as NLRP3, GSDMD, and IL-1β) in H9c2 cells triggered by LPS. CONCLUSION: Taken together, CAR exhibited potential cardioprotective effects against sepsis, which may be mainly attributed to the TLR4/MyD88/NF-κB pathway and the NLRP3 inflammasome.
J Inflamm (Lond)
· 2024 Nov · PMID 39533297
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Transfer RNA-derived small RNAs (tsRNAs) are a newly discovered class of small noncoding RNAs (sncRNAs) that include tRNA-derived stress-induced RNAs (tiRNAs) and tRNA-derived fragments (tRFs). Following the development...Transfer RNA-derived small RNAs (tsRNAs) are a newly discovered class of small noncoding RNAs (sncRNAs) that include tRNA-derived stress-induced RNAs (tiRNAs) and tRNA-derived fragments (tRFs). Following the development of high-throughput sequencing technology, an increasing number of tsRNAs have been discovered with vital functions in different physiological and pathophysiological processes. Extensive research has revealed that tsRNAs are involved in various diseases, such as cancers, autoimmune illnesses and other diseases. This review focuses on the role and significance of tsRNAs in inflammation, such as the regulation of substances including inflammatory inducers, inflammatory cells and inflammatory factors, which contribute to the pathogenesis of inflammation-related diseases. Moreover, we discuss in-depth the molecular pathogenic mechanisms of tsRNAs in inflammation-related diseases through different signaling pathways and assess their clinical value, providing new perspectives for the exploration of tsRNA functions and inflammation-related diseases.
Gu S, Xue Y, Liu X
… +9 more, Tang Y, Wang D, Wu D, Yao M, Xia Z, Yang S, Cai G, Xue S, Dou D
J Inflamm (Lond)
· 2024 Nov · PMID 39501249
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Qingdai (QD), derived from various plant sources, is commonly used in traditional Chinese medicine for ulcerative colitis (UC) treatment. However, the clinical efficacy and mechanisms of orally administered QD remain unc...Qingdai (QD), derived from various plant sources, is commonly used in traditional Chinese medicine for ulcerative colitis (UC) treatment. However, the clinical efficacy and mechanisms of orally administered QD remain unclear. This study aims to evaluate QD's efficacy in UC treatment and uncover its active components and mechanisms. A randomized controlled trial compared QD to Adisa, followed by UPLC-Q-TOF/MS and network pharmacology analyses to identify QD's core components and targets. In vivo experiments on a UC mouse model explored QD's impact on the AHR-Th17/Treg pathway using PCR, WB, ELISA, and flow cytometry. Results showed QD's efficacy in UC treatment, with mucosal healing and remission comparable to Adisa. UPLC-Q-TOF/MS identified 16 core components in mouse colon tissue, with network pharmacology revealing 67 targets, potentially involving the IL-17 signaling pathway and Th17 cell differentiation. QD and its components up-regulated AHR, CYP1A1, and Foxp3, while down-regulating RORγt. Additionally, QD modulated pro-inflammatory (IL-6, IL-17 A) and anti-inflammatory (IL-10, TGF-β1) factors, and Treg/Th17 cell ratios in LPMC. Oral QD administration effectively promoted mucosal healing and improved UC symptoms, potentially through AHR-Th17/Treg pathway regulation.
Bannazadeh Baghi H, Bayat M, Mehrasa P
… +9 more, Alavi SMA, Lotfalizadeh MH, Memar MY, Taghavi SP, Zarepour F, Hamblin MR, Sadri Nahand J, Hashemian SMR, Mirzaei H
J Inflamm (Lond)
· 2024 Nov · PMID 39497125
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Viral infections in humans often cause excessive inflammation. In some viral infections, inflammation can be serious and even fatal, while in other infections it can promote viral clearance. Viruses can escape from the h...Viral infections in humans often cause excessive inflammation. In some viral infections, inflammation can be serious and even fatal, while in other infections it can promote viral clearance. Viruses can escape from the host immune system via regulating inflammatory pathways, thus worsening the illness. MicroRNAs (miRNAs) are tiny non-coding RNA molecules expressed within diverse tissues as well as cells and are engaged in different normal pathological and physiological pathways. Emerging proof suggests that miRNAs can impact innate and adaptive immunity, inflammatory responses, cell invasion, and the progression of viral infections. We discuss some intriguing new findings in the current work, focusing on the impacts of different miRNAs on host inflammatory responses and virus-mediated inflammation. A better understanding of dysregulated miRNAs in viral infections could improve the identification, prevention, and treatment of several serious diseases.
J Inflamm (Lond)
· 2024 Oct · PMID 39482718
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BACKGROUND: T lymphocyte helper (Th) 2 plays the main role in pathogenesis of allergic airway diseases (AAD). Recent studies showed that interleukin (IL) 33, Th17 and Th22 also may be involved in allergic inflammation. T...BACKGROUND: T lymphocyte helper (Th) 2 plays the main role in pathogenesis of allergic airway diseases (AAD). Recent studies showed that interleukin (IL) 33, Th17 and Th22 also may be involved in allergic inflammation. The aim is to evaluate cytokine level before and after nasal challenge with Dermatophagoides pteronyssinus in patients with AAD. METHODS: Patients with persistent allergic rhinitis (AR) with or without allergic asthma (AA) allergic to house dust mite and healthy individuals underwent nasal challenge with Dermatophagoides pteronyssinus. Measurements of IL-13, IL-17, IL-22 and IL-33 in serum and nasal lavage were performed before, 2 and 22 h after nasal challenge by ELISA. RESULTS: . Ten patients with AR only, 6 patients with AR and AA and 7 healthy individuals were involved in the study. Serum IL-22 level significantly increased in patients with AR and AA and nasal lavage IL-22 tended to increase in patients with AAD after nasal challenge. Serum IL-13 level tended to increase in patients with AR and AA. IL-13 level in nasal lavage fluid decreased at 22 h after nasal challenge in patients with AR only. IL-17 level in serum and nasal lavage decreased in patients with AAD. Serum IL-33 tended to increase after nasal challenge whereas IL-33 in nasal lavage significantly decreased. CONCLUSION: Cytokine profile differs between local and systemic compartments and between patients with allergic rhinitis only and patients with allergic rhinitis and asthma after nasal challenge.
Hur J, Rhee CK, Yoon HK
… +5 more, Park CK, Lim JU, An TJ, Choi JY, Jo YS
J Inflamm (Lond)
· 2024 Nov · PMID 39487493
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BACKGROUND: Air pollution, notably particulate matter (PM), significantly impacts chronic respiratory disease such chronic obstructive pulmonary disease (COPD). Although asthma-COPD overlap (ACO), considered one of the C...BACKGROUND: Air pollution, notably particulate matter (PM), significantly impacts chronic respiratory disease such chronic obstructive pulmonary disease (COPD). Although asthma-COPD overlap (ACO), considered one of the COPD etiotype, is associated with greater severity in both symptoms and outcomes, effects of PM exposure remain unclear. Thus, this study aimed to evaluate impact of PM on chronic airway disease animal models. METHODS: We established two distinct COPD etiotypes, cigarette smoking-related COPD (COPD-C) and COPD with asthma (COPD-A), using porcine pancreatic elastase (PPE) for COPD-C and a combination of PPE with ovalbumin for COPD-A. To reflect smoking influence, cigarette smoking extract was administered to both disease models. To assess impact of PM exposure, bronchoalveolar lavage fluid (BALF), proinflammatory cytokines, lung histology, and cellular damage mechanisms were analyzed. RESULTS: In the COPD-A model, cell counts and type 2 cytokines were elevated in BALF independent of PM exposure. All models exhibited increased lung inflammation and emphysema due to PM exposure. Expression levels of apoptosis-related protein B-cell lymphoma protein 2 (Bcl-2) associated X (Bax) showed an inclination to increase with PM exposure. In the COPD-A model, decreased expression of basal nuclear factor erythroid-derived 2-like 2 (Nrf-2) and increased production of reactive oxygen species (ROS) due to PM exposure were noted. CONCLUSION: We developed two distinct models for the etiotypes of COPD and found increased vulnerability to cell damage in COPD-A after PM exposure. Moreover, the control group displayed escalated airway inflammation and emphysema due to PM exposure, substantiating the risk of respiratory diseases.
Guenther T, Coulibaly A, Velásquez SY
… +6 more, Schulte J, Fuderer T, Sturm T, Hahn B, Thiel M, Lindner HA
J Inflamm (Lond)
· 2024 Oct · PMID 39434093
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BACKGROUND: Trauma and infection induce emergency granulopoiesis. Counts of immature granulocytes and transcriptional pathways of terminal granulocytic differentiation in blood are elevated in sepsis but correlate with d...BACKGROUND: Trauma and infection induce emergency granulopoiesis. Counts of immature granulocytes and transcriptional pathways of terminal granulocytic differentiation in blood are elevated in sepsis but correlate with disease severity. This limits their performance as sepsis biomarkers in critically ill patients. We hypothesized that activation of these pathways in sepsis is attributable to immature low-density (LD) rather than mature high-density (HD) granulocytes. METHODS: We included patients with sepsis and systemic inflammatory response syndrome (SIRS) of comparable disease severity, and additionally septic shock, on intensive or intermediate care unit admission. Blood granulocyte isolation by CD15 MicroBeads was followed by density-gradient centrifugation. Flow cytometry was used to determine counts of developmental stages (precursors) and their relative abundancies in total, HD, and LD granulocytes. Five degranulation markers were quantified in plasma by multiplex immunoassays. A set of 135 genes mapping granulocyte differentiation was assayed by QuantiGene™ Plex. CEACAM4, PLAC8, and CD63 were analyzed by qRT-PCR. Nonparametric statistical tests were applied. RESULTS: Precursor counts appeared higher in sepsis than SIRS but did not correlate with disease severity for early immature and mature granulocytes. Precursor subpopulations were enriched at least ten-fold in LD over HD granulocytes without sepsis-SIRS differences. Degranulation markers in blood were comparable in sepsis and SIRS. Higher expression of early developmental genes in sepsis than SIRS was more pronounced in LD and less in HD than total granulocytes. Only the cell membrane protein encoding genes CXCR2 and CEACAM4 were more highly expressed in SIRS than sepsis. By qRT-PCR, the azurophilic granule genes CD63 and PLAC8 showed higher sepsis than SIRS levels in LD granulocytes and PLAC8 also in total granulocytes where its discriminatory performance resembled C-reactive protein (CRP). CONCLUSIONS: Transcriptional programs of early terminal granulocytic differentiation distinguish sepsis from SIRS due to both higher counts of immature granulocytes and elevated expression of early developmental genes in sepsis. The sustained expression of PLAC8 in mature granulocytes likely accounts for its selection in the whole blood SeptiCyte™ LAB test. Total granulocyte PLAC8 rivals CRP as sepsis biomarker. However, infection-specific transcriptional pathways, that differentiate sepsis from sterile stress-induced granulocytosis more reliably than CRP, remain to be identified.
Carregosa D, Loncarevic-Vasiljkovic N, Feliciano R
… +3 more, Moura-Louro D, Mendes CS, Dos Santos CN
J Inflamm (Lond)
· 2024 Oct · PMID 39379968
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Lipopolysaccharide (LPS) challenge in mice has been used to identify the mechanisms and therapeutics for neuroinflammation. In this study, we aimed to comprehensively evaluate the behavioral changes including locomotion,...Lipopolysaccharide (LPS) challenge in mice has been used to identify the mechanisms and therapeutics for neuroinflammation. In this study, we aimed to comprehensively evaluate the behavioral changes including locomotion, exploration, and memory, correlating them with a panel of thirteen inflammatory cytokines in both blood and brain.We found that acute LPS administration (0.83 mg/Kg i.p.) reduced body weight, food intake, and glucose levels compared to the saline-injected mice, concomitant with decreased activity in home cage monitoring. Locomotion was significantly reduced in Open Field, Introduced Object, and Y-Maze tests. Decreased exploratory behavior in the Y-Maze and Introduced Object tests was noticed, by measuring the number of arms explored and object interaction time, respectively. Additionally, in rotarod, LPS administration led to a significant decrease in the distance achieved, while in the MouseWalker, LPS led to a reduction in average velocity.LPS induced a decrease in microglia ramification index in the motor cortex and the striatum, while surprisingly a reduction in microglia number was observed in the motor cortex.The concentrations of thirteen cytokines in the blood were significantly altered, while only CXCL1, CCL22, CCL17, G-CSF, and IL-12p40 were changed in the brain. Correlations between cytokine levels in blood and brain were found, most notably for CCL17 and CCL22. TGFβ was the only one with negative correlations to other cytokines. Correlations between cytokines and behavior changes were also disclosed, especially for CCL17, CCL22, G-CSF, and IL-6 and negatively for TGFβ and IL-10.In summary, our study employing acute LPS challenge in mice has revealed a comprehensive profile of behavioral alterations alongside significant changes in inflammatory cytokine levels, both in peripheral blood and brain tissue. These findings contribute to a deeper understanding of the interplay between inflammation and behavior, with possible implications for identifying prognostics and therapeutic targets for neuroinflammatory conditions.
Li X, Zhou W, Chen J
… +4 more, Zhou L, Li Y, Wu X, Peng X
J Inflamm (Lond)
· 2024 Sep · PMID 39289683
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BACKGROUND: The kidney is exceptionally vulnerable during sepsis, often resulting in sepsis-associated acute kidney injury (SA-AKI), a condition that not only escalates morbidity but also significantly raises sepsis-rela...BACKGROUND: The kidney is exceptionally vulnerable during sepsis, often resulting in sepsis-associated acute kidney injury (SA-AKI), a condition that not only escalates morbidity but also significantly raises sepsis-related mortality rates. Circular RNA circ_001653 has been previously reported to be upregulated in the serum of SA-AKI patients, while the role and underlying mechanism of circ_001653 in SA-AKI remains unknown. In this study, we aimed to explore the functional role and the molecular mechanism of circ_001653 in the pathogenesis of SA-AKI. METHODS: LPS-stimulated HK-2 cells and ligation and perforation of cecum (CLP)-induced rats were used as in vitro and in vivo models of SA-AKI. The target gene expression levels were measured using qRT-PCR and western blot. Renal function (BUN, sCr, uNGAL, and uKIM-1), and renal pathological changes were detected in septic mice. TUNEL and EdU assays were conducted to measure apoptosis and proliferation rates in vitro. DCFH-DA staining was used to detect ROS levels in vitro and in vivo. Oxidative stress markers (SOD, GSH-Px, MDA, and SOD), and inflammation markers (IL-1β, IL-6, and TNF-α) were determined using commercial kits both in vitro and in vivo. Additionally, gain-and-loss-of-function assays and mechanistic experiments were conducted to explore the regulatory role of circ_001653 in SA-AKI pathogenesis. RESULTS: Data showed that circ_001653 expression was high in LPS-stimulated HK-2 cells and CLP-induced rat renal tissue and was mainly localized in the cytoplasm. Notably, circ_001653 silencing alleviated SA-AKI by reducing apoptosis and alleviating oxidative stress and inflammation in HK-2 cells and renal tissue of rats. Mechanistically, it was found that circ_001653 alleviated SA-AKI by recruiting BUD13 to activate the KEAP1/Nrf2/HO-1 signaling pathway. CONCLUSIONS: To summarize, our study is the first to reveal elevated expression of circ_001653 in sepsis-associated AKI, and its downregulation effectively attenuates AKI by reducing apoptosis, inflammation, and oxidative stress. Mechanistically, circ_001653 exerts its effects by recruiting BUD13 to activate the KEAP1/Nrf2/HO-1 signaling pathway. These findings suggest circ_001653 as a potential therapeutic target for the drug development of sepsis-associated AKI.