BackgroundAsthma is a chronic inflammatory disease characterized by airway remodeling and immune dysregulation. This study aimed to explore the mechanisms by which M2 macrophage-derived exosomes (M2Φ-Exos) regulate airway inflammation in asthma by modulating epithelial cell proliferation and apoptosis.MethodsM2Φ-Exos were extracted and characterized by morphology, size, and marker protein expression. In vitro, the effects of M2Φ-Exos on House Dust Mites (HDM)-stimulated mouse lung epithelial cells (MLE-12s) were evaluated using western blotting to analyze Proliferating Cell Nuclear Antigen (PCNA), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase-3 expression. In vivo, M2Φ-Exos were administered to HDM-induced asthmatic mice to assess their impact on airway inflammation, epithelial remodeling, and proliferation-apoptosis balance using immunohistochemistry, immunofluorescence, and western blotting. Cytokine levels in lung tissue and bronchoalveolar lavage fluid (BALF) were measured by qRT-PCR and ELISA.ResultsM2Φ-Exos displayed typical cup-shaped morphology, an average diameter of 115.5 nm, and expressed marker proteins CD9, TSG101, and CD63. MLE-12 cells internalized M2Φ-Exos, leading to reduced abnormal proliferation and apoptosis in HDM-stimulated cells. In asthmatic mice, M2Φ-Exos alleviated airway inflammation and epithelial thickening while reducing PCNA, cleaved caspase-3, and Bax levels and increasing Bcl-2 expression. M2Φ-Exos suppressed pro-inflammatory cytokines (IL-4, IL-5, IL-13) and Transforming growth factor (TGF)-β, while enhancing anti-inflammatory cytokine IFN-γ and IL-10.ConclusionThese findings demonstrate that M2Φ-Exos regulate the imbalance in epithelial proliferation and apoptosis in asthma, reducing inflammation and mitigating tissue remodeling, and provide new insights into potential therapeutic strategies for asthma management.

Several studies have demonstrated that the pulmonary immune response is primarily facilitated by antigen-presenting cells (APCs), and that both professional and non-professional APCs contribute to overall pulmonary immunity. APCs play unique roles and mechanisms in pathogen elimination and immunomodulation. Mucosal immunity exhibits potential advantages over traditional parenteral immunity in that it stimulates immune defenses in mucosal and systemic tissues, which is important for reducing the burden of lung disease. However, obtaining a comprehensive understanding of the crosstalk between mucosal immunity and APC in the context of various lung diseases remains challenging. This mini-review aimed to elucidate the mechanisms of novel mucosal immunity, targeting APC action during lung infections, allergies, and malignant tumorigenesis. This minreview provides important insights into more effective therapeutic approaches for various lung diseases.

Background and AimAcetaminophen (APAP) induced acute liver injury (ALI), the leading cause acute liver failure in the western world, has limited treatment options. APAP toxicity results in massive hepatic necrosis and secondary infiltrating monocytes and neutrophils, which contribute to pathogenesis. Semaphorin 7a (Sema7a), a chemoattractant and modulator of monocytes and neutrophils, is a potential therapeutic target in other conditions, but its role in APAP-ALI is unexplored.MethodsWild-type (WT) and Sema7a knockout (KO) mice were examined during APAP-ALI. Serum liver function tests, histological analysis and cellular localisation of Sema7a and its receptors, Plexin C1 and Integrin β1, were examined. Serum cytokines were quantified, tissue macrophages and neutrophils were localised, and in vivo phenotype, including phagocytosis, was assessed by immunohistochemistry and flow cytometry.ResultsSema7a was expressed by HNF4α + peri-necrotic hepatocytes circumferentially during APAP-ALI injury phases, and serum concentrations were increased, and correlated with hepatic injury. Sema7a KO mice had increased circulating inflammatory cytokines and significantly less hepatic F4/80 + macrophages, a cell type required for hepatic repair. Sema7a KO mice had higher necrotic area neutrophils, and increased neutrophil chemoattractant CXCL1. Without Sema7a expression, mice displayed increased necrosis and liver injury markers compared to Sema7a WT mice. Without peri-necrotic hepatocyte Sema7a expression, we also identified increased cell death and hepatic cellular stress outside of necrosis.ConclusionWe have identified a novel protective role of Sema7a during injury phases of APAP-ALI. Without peri-necrotic hepatocyte Sema7a expression and secretion, there is increased inflammation, time specific worsened hepatic necrosis and increased hepatic cell stress and death outside of the necrotic zone.Graphical

BackgroundHMG-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.MethodScopus 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.ResultsThe 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.ConclusionCCL2 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.

BackgroundSepsis-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.ResultsH9c2 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.ConclusionTaken together, CAR exhibited potential cardioprotective effects against sepsis, which may be mainly attributed to the TLR4/MyD88/NF-κB pathway and the NLRP3 inflammasome.

BackgroundT 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.MethodsPatients 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.ConclusionCytokine profile differs between local and systemic compartments and between patients with allergic rhinitis only and patients with allergic rhinitis and asthma after nasal challenge.

BackgroundRheumatoid arthritis (RA) is associated with a high concentration of extracellular DNA (ecDNA). This could be a consequence of the inflammation, but the ecDNA could also be involved in the unknown etiopathogenesis of RA. Clearance of ecDNA is hypothesized to prevent the development of RA. This study aimed to analyze the effects of exogenous deoxyribonuclease I (DNase I) administration in an animal model of RA.MethodsThe collagen antibody-induced arthritis (CAIA) model of RA was induced in adult female DBA/1J mice. CAIA mice were treated with saline or DNase I (10 mg/kg) every 12 h for the whole duration of the experiment. Arthritic scores were assessed. Paw volume and temperature were assessed using a plethysmometer and a thermal camera, respectively. Plasma ecDNA and its subcellular origin were analyzed using fluorometry and real-time PCR. DNase activity was quantified with single radial enzyme diffusion method.ResultsThe CAIA model was successfully induced as proved by a higher volume, temperature and the overall arthritis score in comparison to controls. The administration of DNase I resulted in a nearly two-fold increase in serum DNase activity. Still, it did affect neither plasma ecDNA, nor the arthritis score or other measures of joint inflammation.ConclusionOur results suggest that exogenous DNase I does not prevent the development of CAIA in mice. Whether this is true for other animal models of arthritis or clinical RA requires further research. EcDNA does not seem to be involved in the pathogenesis of CAIA. Additional studies are also needed to elucidate the role of ecDNA in the development of RA, focusing especially on its origin and inhibition of ecDNA release.

BackgroundInflammation and neuroinflammation are integral to the progression and severity of many diseases and are strongly associated with cardiovascular disease, cancer, autoimmune disorders, neurodegenerative disease, and neuropsychiatric disorders. These diseases can be difficult to treat without addressing the underlying inflammation, and, as such, a growing need has arisen for pharmaceutical treatments that target inflammatory mediators and signaling pathways. Our lab has investigated the therapeutic potential of the irreversible µ-opioid antagonist β-funaltrexamine (β-FNA) and discovered that acute treatment ameliorates inflammation in astrocytes in vitro and inhibits central and peripheral inflammation and reduces anxiety- and sickness-like behavior in male C57BL/6J mice. Now, our investigation has expanded to investigate the chronic pre-treatment effects of β-FNA on lipopolysaccharide (LPS)-induced inflammation and behavior in male C57BL/6J mice.ResultsMicro-osmotic drug pumps were surgically inserted into the subcutaneous intrascapular space of male C57BL/6J mice. β-FNA or saline vehicle was continuously administered for seven days. On the sixth day, mice were given intraperitoneal injections of LPS or saline. An elevated plus maze test, followed by a forced swim test, were administered 24 h post-injection to measure sickness-, anxiety- and depressive-like behavior. Immediately after testing, frontal cortex, hippocampus, spleen, and plasma were collected. Levels of inflammatory chemokines C–C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) were measured in tissues by enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to assess expression of the enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) and the NLR family pyrin domain-containing protein 3 (NRLP3) inflammasome in frontal cortex and spleen tissues. Chronic pre-treatment robustly decreased inflammation in the hippocampus, frontal cortex, and spleen and reduced or abolished anxiety- and sickness-like behavior (e.g., increased time spent motionless, increased time spent in a contracted position, and reduced distance moved). However, treatment with β-FNA alone increased both inflammation in the frontal cortex and anxiety-like behavior.ConclusionThese findings provide novel insights into the anti-inflammatory and behavior-modifying effects of chronic β-FNA pre-treatment and continue to support the therapeutic potential of β-FNA under inflammatory conditions.

BackgroundAtherosclerosis is a chronic inflammatory condition affecting the large arteries and is a major cause of cardiovascular diseases (CVDs) globally. Increased levels of adhesion molecules in cardiac tissue serve as prognostic markers for coronary artery occlusion risk. Given the antioxidant properties of bilirubin and its inverse correlation with atherosclerosis, this study aimed to assess the beneficial effects of bilirubin on atherosclerotic indices and heart structure in high-fat diet-fed diabetic rats with atherosclerosis.MethodsAtherosclerosis was induced in three out of five groups of adult male Sprague Dawley rats through a 14-week period of high-fat diet (HFD) consumption and a single low dose of streptozotocin (STZ) (35 mg/kg). The atherosclerotic rats were then treated with intraperitoneal administration of 10 mg/kg/day bilirubin for either 6 or 14 weeks (treated and protected groups, respectively), or the vehicle. Two additional groups served as the control and bilirubin-treated rats. Subsequently, the mRNA expression levels of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), lectin-like LDL receptor 1 (LOX-1), and the inducible nitric oxide synthase (iNOS) were analyzed using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Histopathological and stereological analyses were performed to assess changes in the heart structure.ResultsBilirubin significantly decreased the expression of VCAM-1, ICAM-1, LOX-1, and iNOS genes in the treated group. Moreover, bilirubin mitigated pathological damage in the left ventricle of the heart. Stereological analysis revealed a decrease in the left ventricle and myocardium volume, accompanied by an increase in vessel volume in rats treated with bilirubin.ConclusionThese findings demonstrate that mild hyperbilirubinemia can protect against the progression of atherosclerosis and heart failure by improving lipid profile, modulating adhesion molecules, LOX-1, and iNOS gene expression levels.