Inflammation Research最新文献

Background: Inflammation serves as our body's immune response to combat infections, pathogens, viruses, and external stimuli. Inflammation can be classified into two types: acute inflammation and chronic inflammation. Non-steroidal anti-inflammatory medications (NSAIDs) are used to treat both acute and chronic inflammatory disorders. However, these treatments have various side effects such as reduced healing efficiency, peptic ulcers, gastrointestinal toxicities, etc. METHOD: This review assesses the potential of anti-inflammatory peptides (AIPs) derived from various natural sources, such as algae, fungi, plants, animals, and marine organisms. Focusing on peptides rich in cysteines and methionine, sulphur-containing amino acids known for their role in suppression of inflammation.

Result: Due to their varied biological activity, ability to penetrate cells, and low cytotoxicity, bioactive peptides have garnered interest as possible therapeutic agents. The utilisation of AIPs has shown great potential in the treatment of disorders associated with inflammation. AIPs can be obtained from diverse natural sources such as algae, fungi, plants, and animals. Cysteine and methionine are sulphur-containing amino acids that aid in the elimination of free radicals, hence assisting in the treatment of inflammatory diseases.

Conclusion: This review specifically examines several sources of AIPs including peptides that contain numerous cysteines and methionine. In addition, the biological characteristics of these amino acids and advancements in peptide delivery are also discussed.

Background: Lymphatic abnormalities are essential for pathophysiologic changes of creeping fat (CrF) in Crohn's disease (CD). Anti-tumor necrosis factor (TNF) therapy has been proved to alleviate CrF lesions, however, whether it achieves these by remodeling lymphatics is unknown.

Methods: CD74 expression was detected in CrF and uninvolved mesentery of CD patients. Lymphatic functions in vitro were evaluated and lymphatic endothelium barrier were checked by transendothelial electrical resistance (TEER) and FITC-Dextran permeability. Protein level of tight junction and signaling pathways were detected by western blotting.

Results: CD74 was upregulated in LECs of CrF and positively correlated with TNF-α synthesis. This was suppressed by IFX administration. In vitro, TNF-α stimulated LECs to express CD74 through NF-κB signaling pathway, and this was rescued by IFX. CD74 downregulation suppressed the abilities of LECs in proliferation, migration and tube formation. Interaction of CD74-MIF impaired LECs' barrier via reducing tight junction proteins in an ERK1/2-dependent manner, which was reversed by CD74 downregulation. Consistently, the CD patients receiving IFX therapy displayed decreased lymphangiogenesis and improved mesenteric lymphatic endothelium barrier, companied with reduced adipocyte size and adipokine levels in CrF.

Conclusions: Anti-TNF therapy could modify pathological changes in CrF by alleviating CD74-mediated lymphatic abnormalities.

Background and aim: Sepsis-induced acute lung injury (ALI) is a complex and life-threatening condition lacking specific and efficient clinical treatments. Extracellular histones, identified as a novel type of damage-associated molecular patterns, have been implicated in the inflammatory process of ALI. However, further elucidation is needed regarding the precise mechanism through which extracellular histones induce inflammation. The aim of this study was to investigate whether extracellular histones can activate NLRP3 inflammasome-mediated inflammation in alveolar macrophages (AMs) by affecting TWIK2-dependent potassium efflux.

Methods and results: We conducted experiments using cecal ligation and puncture (CLP) C57BL/6 mice and extracellular histone-stimulated LPS-primed MH-S cells. The results demonstrated a significant increase in the levels of extracellular histones in the plasma and bronchoalveolar lavage fluid (BALF) of CLP mice. Furthermore, neutralizing extracellular histone mitigated lung injury and inflammation in CLP-induced ALI mice. In vitro studies confirmed that extracellular histones upregulated the expression of NLRP3 inflammasome activation-related proteins in MH-S cells, and this effect was dependent on increased potassium efflux mediated by the TWIK2 channel on the plasma membrane. Moreover, extracellular histones directly triggered a substantial influx of calcium, leading to increased Rab11 activity and facilitating the trafficking and location of TWIK2 to the plasma membrane.

Conclusion: These findings underscore the critical role of extracellular histone-induced upregulation of TWIK2 expression on the plasma membrane of alveolar macrophages (AMs). This upregulation leads to potassium efflux and subsequent activation of the NLRP3 inflammasome, ultimately exacerbating lung inflammation and injury during sepsis.

Background: We have previously shown that asthma-like airways inflammation may be induced by topical exposure to respiratory tract pathogens such as S. pneumoniae (SP) in concert with epithelial alarmins such as IL-33. Details of the pathogenesis of this murine surrogate remain however unexplored.

Methods: Airways inflammation was induced by repeated, intranasal exposure of Il-4^-/-, Rag1^-/- and Rag2^-/-Il2rg^-/- mice (in which B lymphocyte IgE switching, adaptive and innate immunity are respectively ablated) as well as wild type mice to inactivated SP, IL-33 or both. Airways pathological changes were analysed, and the subsets and functions of locally accumulated ILC2s investigated by single cell RNA sequencing and flow cytometry.

Results: In the presence of IL-33, repeated exposure of the airways to inactivated SP caused marked eosinophil- and neutrophil-rich inflammation and local accumulation of ILC2s, which was retained in the Il-4^-/- and Rag1^-/- deficient mice but abolished in the Rag2^-/-Il2rg^-/- mice, an effect partly reversed by adoptive transfer of ILC2s. Single cell sequencing analysis of ILC2s recruited following SP and IL-33 exposure revealed a Klrg1⁺Ly6a⁺subset, expressing particularly elevated quantities of the pro-inflammatory cytokine IL-6, type 2 cytokines (IL-5 and IL-13) and MHC class II molecules, promoting type 2 inflammation as well as involved in neutrophil-mediated inflammatory responses.

Conclusion: Local accumulation of KLRG1⁺Ly6a⁺ ILC2s in the lung tissue is a critical aspect of the pathogenesis of airways eosinophilic and neutrophil-rich inflammation induced by repeated exposure to SP in the presence of the epithelial alarmin IL-33.

Objective: Resident immune cells are at the forefront of sensory organ-specific signals, and changes in these cells are closely related to the aging process. The Sirt pathway can regulate NAD + metabolism during aging, thereby affecting the accumulation of ROS. However, the role of the Sirt pathway in resident immune cells in aged tissues is currently unclear.

Methods: We investigated Sirt1 signalling in resident immune cells during chronic inflammation in an aged mouse model. Integrated single-cell RNA sequencing data from young and aged mice were used to refine the characterization of immune cells in aged tissues RESULTS: We found that C1q + macrophages could affect chronic inflammation during aging. C1q + macrophages acted in an opposing manner to Il1b + macrophages and were responsible for anti-inflammatory effects during aging. Sirt1 agonists inhibited the decrease in C1qb in macrophages during aging, and anti-aging drugs could affect the expression of C1qb in macrophages via the Sirt1 pathway.

Conclusions: In this study, we first identified the relevance of C1q + macrophages in chronic inflammation during aging. The potential anti-aging effect of C1q + macrophages was mediated by the Sirt1 pathway, suggesting new strategies for aging immunotherapy.

Objective: Immunotherapy targeting programmed cell death 1 (PDCD1 or PD-1) and its ligands has shown remarkable promise and the regulation mechanism of PD-1 expression has received arising attention in recent years. PDCD1 exon 3 encodes the transmembrane domain and the deletion of exon 3 produces a soluble protein isoform of PD-1 (sPD-1), which can enhance immune response by competing with full-length PD-1 protein (flPD-1 or surface PD-1) on T cell surface. However, the mechanism of PDCD1 exon 3 skipping is unclear.

Methods: The online SpliceAid program and minigene expression system were used to analyze potential splicing factors involved in the splicing event of PDCD1 exon 3. The potential binding motifs of heterogeneous nuclear ribonucleoprotein K (HNRNPK) on exon 3 predicted by SpliceAid were mutated by site-directed mutagenesis technology, which were further verified by pulldown assay. Antisense oligonucleotides (ASOs) targeting the exonic splicing silencer (ESS) on PDCD1 exon 3 were synthesized and screened to suppress the skipping of exon 3. The alternative splicing of PDCD1 exon 3 was analyzed by semiquantitative reverse transcription PCR. Western blot and flow cytometry were performed to detect the surface PD-1 expression in T cells.

Results: HNRNPK was screened as a key splicing factor that promoted PDCD1 exon 3 skipping, causing a decrease in flPD-1 expression on T cell membrane and an increase in sPD-1 expression. Mechanically, a key ESS has been identified on exon 3 and can be bound by HNRNPK protein to promote exon 3 skipping. Blocking the interaction between ESS and HNRNPK with an ASO significantly reduced exon 3 skipping. Importantly, HNRNPK can promote exon 3 skipping of mouse Pdcd1 gene as well.

Conclusions: Our study revealed a novel evolutionarily conserved regulatory mechanism of PD-1 expression. The splicing factor HNRNPK markedly promoted PDCD1 exon 3 skipping by binding to the ESS on PDCD1 exon 3, resulting in decreased expression of flPD-1 and increased expression of sPD-1 in T cells.

Objective: Poorly controlled diabetes frequently exacerbates lung infection, thereby complicating treatment strategies. Recent studies have shown that exendin-4 exhibits not only hypoglycemic but also anti-inflammatory properties. This study aimed to explore the role of exendin-4 in lung infection with diabetes, as well as its association with NOD1/NF-κB and the T1R2/T1R3 sweet taste receptor.

Methods: 16HBE human bronchial epithelial cells cultured with 20 mM glucose were stimulated with lipopolysaccharide (LPS) isolated from Pseudomonas aeruginosa (PA). Furthermore, Sprague‒Dawley rats were fed a high-fat diet, followed by intraperitoneal injection of streptozotocin and intratracheal instillation of PA. The levels of TNF-α, IL-1β and IL-6 were evaluated using ELISAs and RT‒qPCR. The expression of T1R2, T1R3, NOD1 and NF-κB p65 was assayed using western blotting and immunofluorescence staining. Pathological changes in the lungs of the rats were observed using hematoxylin and eosin (H&E) staining.

Results: At the same dose of LPS, the 20 mM glucose group produced more proinflammatory cytokines (TNF-α, IL-1β and IL-6) and had higher levels of T1R2, T1R3, NOD1 and NF-κB p65 than the normal control group (with 5.6 mM glucose). However, preintervention with exendin-4 significantly reduced the levels of the aforementioned proinflammatory cytokines and signaling molecules. Similarly, diabetic rats infected with PA exhibited increased levels of proinflammatory cytokines in their lungs and increased expression of T1R2, T1R3, NOD1 and NF-κB p65, and these effects were reversed by exendin-4.

Conclusions: Diabetic hyperglycemia can exacerbate inflammation during lung infection, promote the increase in NOD1/NF-κB, and promote T1R2/T1R3. Exendin-4 can ameliorate PA-related pneumonia with diabetes and overexpression of NOD1/NF-κB. Additionally, exendin-4 suppresses T1R2/T1R3, potentially through its hypoglycemic effect or through a direct mechanism. The correlation between heightened expression of T1R2/T1R3 and an intensified inflammatory response in lung infection with diabetes requires further investigation.

Introduction: Inflammation and oxidative stress are key factors in the development of pulmonary fibrosis (PF) by promoting the differentiation of fibroblasts through modulating various pathways including Wnt/β-catenin, TGF-β and mTOR signalling.

Objective and methods: This study aimed to evaluate the effects and elucidate the mechanisms of vistusertib (VSB) in treating pulmonary inflammation/fibrosis, specifically by targeting the mTOR pathway using various in vitro and in vivo models.

Results: Lipopolysaccharide (LPS)-induced inflammation model in macrophages (RAW 264.7), epithelial (BEAS-2B) and endothelial (HMVEC-L) cells revealed that treatment with VSB significantly reduced the IL-6, TNF-α, CCL2, and CCL7 expression. TGF-β induced differentiation was also significantly reduced upon VSB treatment in fibrotic cells (LL29 and DHLF). Further, bleomycin-induced inflammation and fibrosis models demonstrated that treatment with VSB significantly ameliorated the severe inflammation, and lung architectural distortion, by reducing the inflammatory markers expression/levels, inflammatory cells and oxidative stress indicators. Further, fibrosis model results exhibited that, VSB treatment significantly reduced the α-SMA, collagen and TGF-β expressions, improved the lung architecture and restored lung functions.

Conclusion: Overall, this study uncovers the anti-inflammatory/anti-fibrotic effects of VSB by modulating the mTOR activation. Although VSB was tested for lung fibrosis, it can be tested for other fibrotic disorders to improve the patient's survival and quality of life.

Background: Previous studies have observed elevated myeloid cells in the peripheral blood of patients with Parkinson's disease (PD), but the causal relationship between them remains to be elucidated. We investigated whether there is a causal relationship between different subtypes of peripheral blood myeloid cells and PD using Mendelian randomization (MR) combined with bioinformatics analysis. Exploring the etiology of PD from the perspective of genetics can remove confounding factors and provide a more reliable theoretical basis for elucidating the pathogenesis of PD.

Methods: Comprehensive two-sample MR analysis and sensitivity analyses were conducted to explore the causal associations between 64 myeloid cell signatures and PD risk. The Venn diagram and protein-protein interaction network analysis of instrumental variables (IV) corresponding genes were used to further investigate the potential mechanism of myeloid cells influencing the pathogenesis of PD.

Results: We investigated the impact of four immunophenotypes on the risk of PD, including Im MDSC% CD33dim HLA DR^- CD66b^- (relative count), CD33dim HLA DR⁺ CD11b⁺% CD33^dim HLA DR⁺ (relative count), and CD11b on Mo MDSC (MFI) and CD11b on CD33br HLA DR⁺ CD14^dim (MFI), while an immunophenotype's protective effect on PD was observed CD45 on Im MDSC (MFI). The results of bioinformatics analysis showed that CD33, NTRK2, PLD2, GRIK2 and RELN had protein interactions with the risk genes of PD.

Conclusions: Our study has demonstrated a close genetic correlation between different subtypes of myeloid cells and PD, providing guidance for early identification and immunotherapeutic development in patients with PD.

Objective: Asthma is an airway inflammatory disease caused by activation of numerous immune cells including macrophages. Bakuchicin (BKC) is known to exhibit anti-inflammatory effects and type 2 T helper (Th2) regulation, but has not been investigated for airway inflammation. This study aimed to evaluate the effects of BKC on airway inflammation and demonstrate the mechanisms of macrophage polarization.

Methods: The anti-inflammatory effects were determined using lipopolysaccharide (LPS)-stimulated macrophages. The ovalbumin (OVA)-induced asthma mouse model was used to evaluate the effects of BKC on airway inflammation and Th2 responses. Moreover, the effect of BKC on macrophage polarization was confirmed in bone marrow-derived macrophages (BMDMs) differentiation.

Results: BKC suppressed nitric oxide production and expression of pro-inflammatory cytokines by inhibiting signaling pathway in LPS-stimulated macrophages. In an OVA-induced asthma model, BKC treatment alleviated histological changes and mast cell infiltration and reduced the levels of eosinophil peroxidase, β-hexosaminidase, and immunoglobulin levels. In addition, BKC alleviated Th2 responses and M2 macrophage populations in bronchoalveolar fluid. In BMDMs, BKC suppressed IL-4-induced M2 macrophage polarization and the expression of M2 markers such as arginase-1 and Fizz-1 through inhibiting sirtuin 2 levels.

Conclusion: BKC could be a drug candidate for the treatment of allergic asthma.