This study investigates the impact of tryptophan substitution on the properties of the Medisin family peptide MS-PT. By substituting hydrophobic amino acids in MS-PT1 with tryptophan, a series of derivative peptides were synthesized. Among them, the 7W peptide stood out with its unique N-terminal random curl and α-helix structure. In vitro, 7W effectively inhibited the secretion of pro-inflammatory cytokines like IL-6 and TNF-α in LPS-induced Membrane-Proximal Macrophages (MPMs) by blocking the MAPK/NF-κB signaling pathway. It also exhibited stronger antimicrobial activity against Gram-positive bacteria compared to the parent peptide MS-PT1, with good safety as indicated by a low hemolysis rate. In vivo, in the CLP-induced sepsis mouse model, 7W alleviated lung and liver injury, suppressed the expression of inflammatory factors in serum and tissues, and had a relatively long plasma half-life of 46.8 h. Mechanistically, 7W interacted preferentially with bacterial mimic membranes and LPS, and its anti-inflammatory effect might be mediated by binding to TLR4. These findings not only clarify the role of tryptophan substitution in modulating peptide properties but also offer a new strategy for the development of multifunctional antimicrobial peptides, suggesting that 7W has great potential as a therapeutic agent for sepsis and other inflammatory diseases.

Thyroid cancer (TC) is the most prevalent endocrine malignancy, with a rising incidence necessitating safer treatment strategies to reduce overtreatment and its side effects. Xiaoyao Powder (XYP), a widely used herbal formula, shows promise in treating TC. This study aims to investigate the mechanisms by which XYP may affect TC.

The components of XYP were identified through database retrieval, and targets related to TC were collected to construct a target network for key screening. GEO dataset samples analyzed immune cells and identified significantly differentially expressed core genes (SDECGs). Based on SDECG expression and clustering, samples were classified for comparison. WGCNA was employed to identify gene modules linked to clinical characteristics. ML models screened characteristic genes and constructed a nomogram validated using another GEO dataset. MR methods explored causal relationships between genes and TC.

The top ten active components of XYP were identified, along with 27 SDECGs that exhibited significant differences in immune cell infiltration between TC patients and normal controls. The nomogram effectively predicted TC risk, validated through ROC curves. Key characteristic genes included SMIM1, PPP1R16A, KIAA1462, DNAJC22, and EFNA5.

XYP may treat TC by regulating SMIM1, PPP1R16A, KIAA1462, DNAJC22, EFNA5, and associated immune pathways; this provides theoretical support for its potential mechanisms.

Astragaloside IV (AS-IV) is a bioactive compound derived from Radix Astragali, a traditional Chinese herb widely used as a dietary supplement to enhance immune function. Modern pharmacological studies have demonstrated that AS-IV exhibits anti-inflammatory and immunomodulatory properties. In this study, we investigated the effects of AS-IV on motor dysfunction, microglial polarization, and immune regulation mechanisms in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Our results showed that AS-IV (40 mg/kg) significantly improved motor function in PD mice, as evidenced by reduced descent time in the pole test, increased hanging score in the hanging test, increased stride lengths, and reduced paw angle in the gait test. Furthermore, AS-IV administration attenuated the loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc), promoted microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, suppressed the levels of pro-inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα), enhanced the levels of anti-inflammatory cytokines including interleukin-4 (IL-4) and interleukin-10 (IL-10) in the SNpc of PD mice. Mechanistically, AS-IV significantly downregulated the expression and phosphorylation levels of TLR4/p38 (JNK)/NF-κB pathway-related proteins, including Toll-like receptor 4 (TLR4), Myeloid differentiation primary response protein 88 (MyD88), Apoptosis signal-regulating kinase 1 (ASK1), Mitogen-activated protein kinase 3/6 (MKK3/6), Phosphorylated-MKK3/6 (p-MKK3/6), Phosphorylated-mitogen-activated protein kinase 4/7 (p-MKK4/7), p38 mitogen-activated protein kinase (p38), Phosphorylated-p38 (p-p38), c-Jun N-terminal kinase (JNK), Phosphorylated-JNK (p-JNK), nuclear factor kappa-B (NF-κB), and Phosphorylated-NF-κB (p-NF-κB). To further validate the targeting effect of AS-IV, 1 mg/kg of LPS-EB Ultrapure was utilized as a specific TLR4 agonistwe to selectively activated the TLR4/NF-κB signaling pathway without triggering other inflammatory pathways, leading to elevated mRNA levels of TLR4, NF-κB, IL-1β, IL-6, TNFα and protein expression of TLR4, p-JNK, p-p38, p-NF-κB, IL-1β, IL-6, TNFα in the SNpc of PD mice. Importantly, AS-IV pretreatment can't counteract these LPS-EB Ultrapure-triggered effects, demonstrating its dependence on the TLR4/NF-κB signaling pathway. In conclusion, our findings indicate that AS-IV modulates microglial polarization and attenuates neuroinflammation by inhibiting the TLR4/NF-κB pathway, thereby ameliorating motor dysfunction and neuronal loss in PD mice.

Actinobacillus pleuropneumoniae (A. pleuropneumoniae), a porcine respiratory tract pathogen, causes porcine pleuropneumonia. Porcine alveolar macrophages (PAMs) play a crucial role during A. pleuropneumoniae infection. Amyloid precursor protein (APP) can be cleaved by β- and γ-secretase to produce β-amyloid (Aβ). APP and Aβ are associated with the inflammatory response. They activate microglia and astrocytes to secrete IL-1β, IL-6, and other cytokines. In this study, we found that during the interaction between A. pleuropneumoniae and PAMs, the two-component system CpxAR upregulates wecA expression, increasing lipopolysaccharide (LPS) production. LPS promotes APP production and cleavage to generate Aβ. The Aβ activates NF-κB, leading to increased IL-1β expression. We hypothesize that A. pleuropneumoniae infection of PAMs regulates APP production and cleavage to control Aβ levels. Different quantities of Aβ induce PAMs to produce varying amounts of cytokines, leading to different pathological processes in porcine pleuropneumonia.

Macrophages are essential for the proliferation and spread of Toxoplasma gondii. Modulating macrophage activation to improve the inflammatory environment is an effective approach for disease treatment. However, the molecular mechanism through which T. gondii alters macrophage function remain unknown. Based on transcriptomic data analysis of various macrophage types infected with T. gondii, current research revealed differences in the regulation of macrophage functions among strains with different virulence: RH was primarily involved in cell cycle regulation, ME49 was associated with cAMP signaling, and CEP mainly participated in ion channel activity. All three T. gondii strains were involved in regulating immune response activation, including leukocyte adhesion and the MAPK signaling pathway. Nineteen shared DEGs associated with macrophage phagocytosis or polarization were identified through the GeneCards database, and PPI analysis confirmed Il6 as the hub gene in the regulatory network. In vivo and in vitro experiments showed that the YZ-1 strain significantly regulated the expressions of eight DEGs (Il6, Rel, Cd83, Myc, Adora2b, Egr2, Gja1 and Nr4a2), and promoted macrophage phagocytic activity and induced M1 polarization, confirming a significant correlation with Il6. This study revealed the dissimilarities and commonalities in macrophage function regulated by T. gondii strains of different virulence, and identified key molecules involved in the regulation of macrophage phagocytosis and polarization during T. gondii infection. This is crucial for identifying potential drug targets against T. gondii and provides a new perspective on the etiopathogenesis and therapeutic approaches for toxoplasmosis.

Obesity and its associated pro-inflammatory activity contribute significantly to metabolic dysfunction. In contrast, browning of white adipose tissue (WAT) generally improves metabolic health. Our prior research suggested that macrophage-derived pro-inflammatory cytokines suppress key regulators of browning-adrenergic receptor β3 (Adrb3) and peroxisome proliferator-activated receptor γ (Pparg)-as well as energy metabolism mediators-insulin receptor substrate 1 (Irs1) and hormone-sensitive lipase (Lipe)-in diet-induced obese mice. To explore this mechanism, we developed an in vitro model using RAW264.7 macrophages and 3T3-L1 adipocytes exposed to palmitic acid (PA) and/or lipopolysaccharide (LPS). PA (200 μM) and LPS (1.0 μg/ml) synergistically promoted M1 polarization of macrophages and secretion of pro-inflammatory cytokines, with tumor necrosis factor-α (TNFα), C-C motif chemokine ligand 2 (CCL2), CCL5, and interleukin-6 (IL-6) being predominant. Conditioned media from both control and PA-treated macrophages, when exposed to LPS ≥0.01 μg/ml, significantly downregulated Adrb3, Pparg, Irs1, and Lipe in adipocytes. At physiologically relevant LPS levels (≤0.001 μg/ml), PA-treated macrophage media exerted greater suppression of these genes than controls. Among the cytokines, TNFα emerged as the primary mediator, significantly reducing expression of the four key regulators. Furthermore, adipocytes treated with TNFα exhibited significant reductions in both uncoupling protein 1 (Ucp1) expression and mitochondrial respiration. These findings demonstrate that exposure to obesity-associated factors (PA and LPS) induces macrophage-derived TNFα, which suppresses browning and mitochondrial function in adipocytes. This mechanism may inform new therapeutic strategies targeting TNFα to alleviate obesity-related metabolic disorders.

Liver fibrosis is a reversible pathophysiological condition characterized by excessive extracellular matrix deposition that can progress to cirrhosis and liver failure if left untreated. Taurine, a sulfur-containing amino acid, protects the liver from damage. However, the effects of taurine on liver fibrogenesis have not been completely elucidated. In this study, we used amino acid metabolomics, gene expression microanalysis, and single-cell RNA sequencing (scRNA-seq) to investigate the roles of taurine, formyl peptide receptor 2 (Fpr2), and proinflammatory macrophages in liver fibrosis in human fibrotic sections and two distinct mouse models of liver fibrosis. Taurine transporter SLC6A6 wild-type and knockout littermate models and critical element inhibitors were also used. We found that taurine levels were significantly reduced in both human and murine fibrotic sections and that exogenous taurine supplementation alleviated fibrosis via SLC6A6. Furthermore, gene expression microarray analysis and scRNA-seq analyses demonstrated that exogenous taurine mitigated liver fibrosis, mainly by regulating Fpr2-related macrophage status. WRW4-mediated inhibition of Fpr2 ameliorated M1 macrophage polarization and alleviated liver fibrosis. Additionally, exogenous taurine suppressed Fpr2-modulated macrophage M1 polarization and the production of associated proinflammatory cytokines by repressing NF-κBp65 phosphorylation; moreover, SLC6A6 deficiency or treatment of liver fibrosis mouse models with an NF-κB inhibitor, BAY, impaired this protective effect of taurine. Therefore, taurine exerts a protective effect against liver fibrosis by repressing Fpr2/NF-κBp65-regulated macrophage M1 polarization, highlighting its potential therapeutic agent.

Macrophages represent a crucial cell type within the immune system, exhibiting significant adaptability that allows for the transformation into various phenotypes in response to their surrounding environment. This review investigates the characteristics of various macrophage phenotypes and their functional roles in disease pathogenesis and resolution. The M1 phenotype, recognized for its inflammatory attributes, plays a pivotal role in combating infections and tumors; however, it may also contribute to tissue injury, persistent inflammation, and the pathogenesis of autoimmune and inflammatory diseases. Conversely, the M2 phenotype is associated with anti-inflammatory activities and tissue repair processes. But this is not the end of the story and researches illustrated novel phenotypes that may provide new approaches and therapeutic opportunities. Recent progress in characterizing distinct macrophage phenotypes has enabled the development of innovative therapeutic strategies for chronic inflammatory conditions, autoimmune disorders, and cancers. This review underscores the critical role of macrophage polarization, illustrating how various stimuli can influence macrophage fate and modify their responses. Additionally, it explores the implications of macrophage plasticity on disease progression and treatment efficacy. A comprehensive understanding of these dynamics is essential for the advancement of targeted immunotherapies, which possess the potential to transform treatment strategies for a variety of medical conditions.

The pathogenesis of autoimmune diseases (AIDs) is complex and their etiology remains unclear, with multiple cell types involved in the disease progression. Macrophages, as a crucial immune cell population in AIDs, play a pivotal role in maintaining immune homeostasis. In traditional research, macrophages are frequently oversimplified into the M1 and M2 polarized subtypes. The advent of single-cell RNA sequencing (scRNA-seq) technology has significantly advanced high-throughput research in the life sciences, enabling in-depth investigations at the cellular and molecular levels. This technology has revealed the significant heterogeneity of macrophages, further enhancing our understanding of their development, phenotypic diversity, and functional plasticity. Additionally, it provides a novel perspective for exploring the molecular mechanisms underlying various diseases. In this review, we comprehensively explore the heterogeneity of macrophages across different AIDs, and summarize potential therapeutic targets for macrophage-directed interventions, aiming to provide valuable theoretical insights and novel research directions to advance precision therapy and related studies in AIDs.

The traditional action of Rabdosia rubescens (Hemsl.) H. Hara is heat-clearing and detoxifying, relieve sore throat, dissipate binds and disperse swelling. DLC, as an extract prepared from Rabdosiae Rubescentis Herba, could regulate the polarization of tumor associated macrophages (TAMs). For TAMs play an important role in the tumor microenvironment. It is worthy to further explore the mechanism of DLC on the polarized function of macrophages.

The aim of this study is to investigate the activity and molecular mechanisms of DLC on dissipating binds and dispersing swelling by modulating the gastric cancer microenvironment and macrophage polarization.

We conducted comprehensive qualitative and quantitative chromatographic analyses to characterize the main components of DLC. To evaluate its anti-tumor effects, immunofluorescence, MTT assay, plate cloning, transcriptomics analysis, western blotting, and siRNA knockdown experiments were performed to assess DLC's action on gastric cancer cell proliferation. Additionally, we utilized Trypan blue staining, a THP-1 and MGC-803 co-culture model, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and a mouse xenograft model with five distinct dosage groups to systematically investigate DLC's effects on macrophage polarization.

Key compounds in DLC were identified. The vivo tests demonstrated the tumor inhibition rate of the 5 g/kg DLC group reached 66.99 %, surpassing that of the 5-fluorouracil group (59.94 %). Mechanistically, DLC upregulated SIRT1 expression and suppressed NF-κB pathway, thereby preventing p65 from translocating into nuclear and modulating downstream p53/MDM2/USP7 signaling. Moreover, DLC enhanced M1 macrophage factors such as TNF-α, IL-6 while inhibiting M2 marker TGF-β, effectively repolarizing M2 TAMs toward an M1 phenotype. This effect was associated with suppressed protein expression of HIF-1α, p-p65, and p-PI3K.

This study provides insights into DLC's mechanisms in regulating tumor microenvironment remodeling and promoting macrophage polarization toward an anti-tumor phenotype. These results provide a solid basis for DLC's potential clinical treament in gastric cancer, highlighting its promise as a natural therapeutic agent.

The ETS transcription factor ELK3 has been identified as a novel oncogene that plays a significant role in the pathological processes and progression of various human cancers. Recent research indicates that ELK3 may serve as a potential prognostic molecular marker for glioma; however, its mechanistic role in glioma remains insufficiently explored.

This study aimed to investigate the impact of ELK3 on glioma prognosis, examine the regulatory influence of IDH1 on ELK3, and assess the role of ELK3 in tumor immune infiltration.

Bioinformatics techniques were employed to identify the gene ELK3, which exhibited significant differential expression and was associated with grading and prognosis in the public database. This finding was validated through immunohistochemistry and RT-qPCR, while the association between ELK3 expression and IDH1 status was confirmed using Western blotting and IHC. Furthermore, ELK3 expression demonstrated a positive correlation with the infiltration of M2 macrophages, as evidenced by immune co-culture studies.

The study identified ELK3 as significantly differentially expressed and associated with tumor grading and prognosis through analyses of public databases. Univariate and multivariate Cox proportional hazards regression analyses established ELK3 as an independent negative prognostic factor. Within The TCGA cohort, a prognostic nomogram was developed by integrating ELK3 with other clinical indicators, and its efficacy was evaluated using ROC curves and calibration curves. The nomogram demonstrated robust performance, with an AUC of no less than 0.9, and showed strong concordance in both internal and external validation cohorts. Furthermore, ELK3 expression was linked to the DNA methylation and mutation status of IDH1. Gene profiling related to ELK3 was constructed, revealing its potential biological functions in immunoregulatory processes through functional enrichment analysis. ELK3 expression exhibited a positive correlation with macrophage and neutrophil infiltration, consistent with findings from the TIMER and spatial transcriptomics. Additionally, ELK3 expression showed a moderate correlation with CD163 expression, suggesting its role in promoting immune infiltration involving M2 macrophages.

ELK3 is a potential prognostic marker for poor outcomes in diffuse glioma and may play a regulatory role in immune infiltration, particularly by enhancing M2 macrophage-mediated immune infiltration.

Macrophage M2 polarization plays a critical role in the progression of endometriosis (EMS), and glycolysis has emerged as a potential therapeutic target. This study aimed to investigate the interplay between glycolytic signaling and macrophage M2 polarization in EMS.

Clinical correlations were analyzed in ectopic endometrial tissues from EMS patients. Primary endometrial stromal cells (ESCs) and Ishikawa cells were cultured under hypoxic conditions, and their conditioned media were used to treat THP-1-derived macrophages. Mechanistic investigations were performed through PDPK1 knockdown, AKT/CD47 overexpression, and lactic acid (LA) supplementation, and the therapeutic potential was assessed in a mouse model of EMS treated with PDPK1, CD47, and LDHA inhibitors.

Ectopic EMS tissues exhibited increased infiltration of CD206+ M2 macrophages, which positively correlated with upregulation of CD47, PDPK1, and LDHA. Hypoxia enhanced the proliferation and migration of endometrial cells, accompanied by activation of the AKT/mTOR pathway and glycolytic reprogramming, as indicated by elevated glucose uptake, LA, and ATP production, and elevated expression of GLUT1, PDK1, and PKM2. Moreover, hypoxia promoted M2 polarization of THP-1-derived macrophages, evidenced by an increased CD206+ population, a disrupted M1/M2 ratio, reduced pro-inflammatory cytokines (IL-6, TNF-α), and elevated anti-inflammatory factors (IL-10, TGF-β). Silencing of PDPK1 attenuated hypoxia-induced AKT/mTOR activation and CD47/LDHA expression, thereby reducing glycolysis and M2 polarization. These effects were restored by AKT/CD47 overexpression or exogenous LA supplementation. In vivo, pharmacological inhibition of PDPK1, CD47, or LDHA significantly reduced lesion size, suppressed M2 macrophage infiltration, and promoted apoptosis.

PDPK1 promotes M2 polarization via CD47/AKT-LDHA-mediated glycolytic reprogramming, thereby exacerbating EMS progression. Targeting this glycolysis-immune axis could be a promising therapeutic strategy for EMS.

With the increasing prevalence of diabetes, diabetic foot ulcers (DFUs) have become a global health challenge, significantly impacting patients' quality of life and placing a substantial burden on healthcare systems. Among various immune cell subsets, M2-polarized macrophages play a pivotal role in tissue repair and inflammation resolution. This study uses single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing to comprehensively investigate the role of the TFAP2A-LIFR-Hippo-YAP signaling axis in regulating macrophage M2 polarization and its critical function in DFU wound healing. Through scRNA-seq analysis, we identified nine major immune cell subsets in DFU samples, with macrophages emerging as key regulatory cells. In vitro experiments further confirmed that TFAP2A promotes macrophage M2 polarization (evidenced by increased expression of the M2 marker ARG1) and ameliorates endothelial dysfunction by enhancing tube formation, improving migration capacity, and upregulating relevant proteins such as VCAM-1. Moreover, TFAP2A serves as a central regulatory gene for macrophage function in DFU by upregulating LIFR expression and activating the Hippo-YAP signaling pathway, thereby inducing M2 polarization and mitigating endothelial dysfunction. Mouse model experiments further demonstrated that the TFAP2A-LIFR-Hippo-YAP signaling axis accelerates DFU wound healing through the induction of macrophage M2 polarization. This study unveils a novel immunoregulatory role of TFAP2A in DFU and provides a promising therapeutic target for the treatment of chronic diabetic wounds.NEW & NOTEWORTHY This study provides unprecedented insights into diabetic foot ulcer healing by demonstrating the novel immunoregulatory role of the TFAP2A-LIFR-Hippo-YAP signaling axis. Leveraging single-cell and bulk transcriptomics, we identify TFAP2A as a crucial regulator of macrophage M2 polarization, essential for wound healing and angiogenesis. These findings offer valuable mechanistic understanding and present TFAP2A as a promising therapeutic target for improving outcomes in chronic diabetic wounds.

The roots of Shuteria involucrata (Wall.) Wight & Arn., known as "Tong-qian-ma-huang" in Dai folk medicine in China, are renowned for their efficacy in treating asthma. Despite the use of S. involucrata has been reported as ameliorating respiratory diseases, its mechanism of action remains unclear. This work described the effect of ethyl acetate extract of S. involucrate (SSE) on allergic asthma and its potential mechanism of action was assessed. Ovalbumin was used in vivo to establish a BALB/c asthma mouse model. Lipopolysaccharide was used in vitro to stimulate the human macrophage cell line THP-1 to establish an inflammatory model. In vivo and in vitro experiments showed that SSE effectively ameliorated pathological symptoms and attenuated airway inflammation and cellular inflammation in allergic asthma mice, with a mechanism of action potentially associated to the inhibition of the TLR4/NF-κB signaling pathway.

Cancer immunotherapy has evolved into a new generation strategy in the field of anti-tumor treatment. Polysaccharides derived from Traditional Chinese Medicine (TCM) are gaining recognition as powerful immunomodulators in cancer therapy, noted for their multi-target and multi-pathway actions. Owing to their beneficial properties such as water solubility, biocompatibility, and chemical structure modifiability, TCM polysaccharides can also serve as carriers for hydrophobic drugs in the development of innovative drug delivery systems, enhancing synergistic antitumor effects. In this article, we summarize the diverse mechanisms of immunoregulation by TCM polysaccharides in tumor therapy. The applications of these polysaccharides as both active ingredients and drug carriers within nanodelivery systems for cancer immunotherapy are also introduced. Additionally, extensive research on TCM polysaccharides in clinical settings has been collected. Furthermore, discussions are presented on the development prospects and challenges faced by these polysaccharides in the field of tumor immunotherapy. Our goal is to improve researchers' comprehension of TCM polysaccharides in cancer immunotherapy, providing promising strategies to optimize cancer treatment and benefit diverse patient populations.

Stromal vascular fraction (SVF) cells and micro-fragmented adipose tissue (MFAT) have potential for treating knee osteoarthritis (OA), but their efficacy has not been compared. This study aimed to compare the clinical outcomes of SVF and MFAT for knee OA. We hypothesized that SVF provides stronger short-term effects, while MFAT offers more sustained benefits.

A retrospective single-center cohort study was conducted on patients with knee OA, with 36 SVF and 36 MFAT cases selected through propensity score matching between September 2017 and February 2022. Patients with KL grades I-IV varus knee OA, significant pain (VAS ≥40), and functional impairment despite conservative treatments were included. Those with knee trauma, severe bony defects, infections, genu valgus, osteonecrosis, rheumatoid arthritis, or severe deformities were excluded. Clinical outcomes were assessed using the visual analog scale, KOOS, knee range of motion, extension/flexion strength, and MRI T2 mapping.

SVF and MFAT groups demonstrated significant improvements in VAS (p < 0.01 for both groups). Both groups showed notable improvements in extension angle, extension/flexion muscle strength, and KOOS, with no significant differences between them. However, the MFAT group demonstrated significantly greater improvement in flexion angle compared to the SVF group (p = 0.03). No serious adverse events were reported. T2 mapping showed significant improvements in cartilage quality in both groups, with the MFAT group demonstrating superior improvements in specific lateral regions. Responder rate in SVF group initially improved but declined over time; however, the MFAT group showed sustained improvement from six months onward.

T2 mapping revealed that MFAT had better cartilage preservation than that of SVF cells in less-loaded areas, with a potentially longer-lasting therapeutic effect. These findings offer important insights for clinicians to tailor treatment strategies based on patient needs and disease progression.

Phagocytosis is a key process in human innate immune response. Human macrophages are important phagocytes engulfing and neutralizing pathogens and cell debris. In addition, they modulate the inflammatory process by releasing cytokines and lipid mediators. However, the link between oxylipins and phagocytosis in different macrophage phenotypes remains poorly understood. In order to better understand the link between phagocytosis and the arachidonic acid (ARA) cascade, we established a phagocytosis assay in primary human 'inflammatory' M1- and 'anti-inflammatory' M2-like macrophages from peripheral blood mononuclear cells (PBMC), representing extremes of macrophage phenotypes. The branches of the ARA cascade were investigated by quantitative targeted proteomics and metabolomics. M1-like macrophages show a higher abundance of cyclooxygenase (COX)-2 and its products particularly after LPS stimulus compared to M2-like macrophages. LPS increased phagocytosis in M2-like, but not in M1-like macrophages. We demonstrate that the COX product prostaglandin E2 (PGE2) modulates the differential effects of LPS on phagocytosis: Via the EP4 receptor PGE2 signaling suppresses phagocytosis in primary human macrophages. Thus, blockage of COX, e.g. by non-steroidal anti-inflammatory drugs (NSAID), leads to an increase of phagocytosis also in 'inflammatory' M1-like macrophages. This supports the well-described anti-inflammatory effects of these drugs and underscores the importance of the link between the COX branch of the ARA cascade and the regulation of phagocytosis in human macrophages.

Streptococcus equi subsp. zooepidemicus (SEZ) is an important pathogen which is responsible for a wide range of diseases in various species. Macrophages are professional phagocytes that can engulf microorganisms and trigger responses leading to microbial death. Caspase-1 is considered as a proinflammatory factor that mediates antibacterial response to protect hosts from bacteria. Here, we revealed a novel role of Caspase-1 in mice against SEZ. Through both in vitro and in vivo infection assays, we demonstrated that the maturation and secretion of the cytokine IL-1β are critically dependent on Caspase-1 activation. The Caspase-1 deficient mice displayed attenuation of bactericidal activity against SEZ, mainly by decreasing the accumulation of macrophage. In addition to the recruitment of macrophages, deficiency of Caspase-1 also impaired the phagocytosis of SEZ by macrophages. Our study demonstrated that Caspase-1 is critical for mice to defense against SEZ depending on the recruitment and phagocytosis of macrophage.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP), contributing significantly to global disability and productivity loss. Its pathogenesis involves complex processes, including inflammation, cellular senescence, angiogenesis, fibrosis, neural ingrowth, and sensitization. Emerging evidence highlights macrophages as central immune regulators infiltrating degenerated discs, with macrophage polarization implicated in IVDD progression. However, the mechanisms linking macrophage polarization to IVDD pathology remain poorly elucidated.

A comprehensive literature review was conducted by searching major databases (PubMed, Web of Science, and Scopus) for studies published in the last decade (2014-2024). Keywords included "intervertebral disc degeneration," "macrophage polarization," "inflammation," "senescence," and "therapeutic strategies." Relevant articles were selected, analyzed, and synthesized to evaluate the role of macrophage polarization in IVDD.

Macrophage polarization dynamically influences IVDD through multiple pathways. Pro-inflammatory M1 macrophages exacerbate disc degeneration by amplifying inflammatory cytokines (e.g., TNF-α, IL-1β), promoting cellular senescence, and stimulating abnormal angiogenesis and neural ingrowth. In contrast, anti-inflammatory M2 macrophages may mitigate degeneration by suppressing inflammation and enhancing tissue repair. Therapeutic strategies targeting macrophage polarization include pharmacological agents (e.g., cytokines, small-molecule inhibitors), biologic therapies, gene editing, and physical interventions. Challenges persist, such as incomplete understanding of polarization triggers, lack of targeted delivery systems, and limited translational success in preclinical models.

Macrophage polarization is a pivotal regulator of IVDD pathology, offering promising therapeutic targets. Future research should focus on elucidating polarization mechanisms, optimizing spatiotemporal control of macrophage phenotypes, and developing personalized therapies. Addressing these challenges may advance innovative strategies to halt or reverse IVDD progression, ultimately improving clinical outcomes for LBP patients.

Thoracic tumours represent a significant proportion of malignant cancers. While radiotherapy (RT) improves prognosis, it can also lead to side effects such as radiation-induced pneumonitis (RP). Since SIRT6 is involved in DNA repair, energy metabolism and inflammation, this study aims to investigate the expression of SIRT6 in lymphocytes as a potential biomarker and therapeutic target for RP. This study included 170 patients diagnosed with thoracic tumours, all of whom underwent thoracic RT. RP was evaluated and classified as severe RP (SRP) and lower as non-severe RP (NSRP). Analyses were performed using SPSS version 26.0 and the R. Among 170 patients in this study, 124 developed NSRP, and 46 experienced SRP. The univariate analysis showed that SIRT6 expression (cOR, 0.33, 95%CI, 0.18-0.97 before RT and 0.31, 0.19-0.98 after RT), clinical factors, dosimetric parameters and haematological/serological parameters were associated with SRP before and after RT. Our multivariable logistic regression showed that SIRT6 expression was significantly associated with risk of SRP before (aOR, 0.32, 95%CI, 0.15-0.96) and after RT (aOR, 0.32, 95%CI, 0.18-0.99) after adjustment with other confounders. Moreover, the receiver operating characteristic curve analysis revealed that the combined multivariable model exhibited superior predictive capability compared to any single predictor (overall AUC, 0.93, 95%CI, 0.90-0.97 before RT and AUC, 0.91, 95%CI, 0.87-0.96 after RT). The expression of SIRT6 alone or in combination with other risk factors was associated with an increased risk of SRP, suggesting a novel approach for the prevention and treatment of radiation pneumonitis in clinical practice.

Acute lung injury (ALI), a severe pulmonary disorder that poses a significant threat to life, is closely associated with macrophage ferroptosis and polarization. Lipocalin 2 (LCN2) has been previously reported to be implicated in the pathogenesis of ALI. However, the specific role of LCN2 in macrophage ferroptosis and polarization remains undetermined. Lipopolysaccharide (LPS) was used to establish a mouse model of ALI and also to stimulate mouse RAW264.7 cells. H&E staining was used for histopathologic evaluation, and immunohistochemistry analysis was used to determine the 4-HNE-positive cells. The secretion levels of TNF-α, IL-6, and IL-1β were assessed by ELISA. Gene and protein expression assays were performed using quantitative PCR and immunoblotting. The levels of MDA, GSH, ROS, and lipid ROS were detected to evaluate the alteration in ferroptosis. CD86+ and CD206+ cells were quantified by flow cytometry. The relationship between LCN2 and interferon regulatory factor 7 (IRF7) was confirmed by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. LCN2 expression was upregulated in the lungs of LPS-induced ALI mice and LPS-stimulated RAW264.7 cells. In LPS-induced ALI mice, the depletion of LCN2 alleviated lung injury and ferroptosis, and also inhibited inflammation and macrophage M1 polarization. In LPS-stimulated RAW264.7 cells, the depletion of LCN2 suppressed ferroptosis, inflammation, and M1 polarization. Mechanistically, IRF7 enhanced LCN2 transcription in RAW264.7 cells by binding to its promoter region. More importantly, the silencing of IRF7 inhibited ferroptosis and M1 polarization in LPS-stimulated RAW264.7 cells by downregulating LCN2. Taken together, the IRF7/LCN2 cascade enhances the ferroptosis and M1 polarization of LPS-stimulated macrophages, thereby exacerbating ALI. Anti-IRF7 and anti-LCN2 therapies might potentially be exploited for the prevention and treatment in ALI.

Compared to traditional tumor treatment modalities, such as radiotherapy, chemotherapy, and surgical intervention, tumor immunotherapy offers potential benefits by enhancing the immune system's functionality, diminish immune evasion, and establish enduring immune memory, ultimately aiming for the destruction or eradication of tumor cells. However, the intricate tumor microenvironment (TME) poses challenges for immunotherapy due to its suppressive effects on immune cell activity, leading to issues such as low immune responsiveness and insufficient targeting. Sonodynamic immunotherapy (SDT) emerges as an innovative therapeutic approach， where sonosensitizers localize around tumor cells and, upon ultrasound (US) stimulation, generate substantial reactive oxygen species (ROS). This mechanism facilitates targeted tumor cell killing and enhances treatment specificity. ROS also induce immunogenic cell death (ICD) through various pathways, bolstering the immune response. Recent research suggests that piezoelectric biomaterials, used as sonosensitizers, can amplify the anti-tumor effects of SDT. The piezoelectric effect of these materials enhances ROS production efficiency, improves the TME, mitigates immune cell suppression, and promotes ICD. This review article provides an overview of piezoelectric biomaterials classification, introduce the piezoelectric effect, and examines the applications of piezoelectric biomaterials in sonodynamic immunotherapy. It serves as a reference for the development of piezoelectric materials and the advancement of tumor treatment strategies.

Acute lung injury (ALI) induced by sepsis is a serious life-threatening disease, one of its characteristics is the polarization of macrophages. Circ_0008285 has been found to be associated with various diseases. In this study, we detected the regulatory role and mechanism of circ_0008285 in sepsis-induced ALI. RAW264.7 cells treated with LPS and C57BL/6 male mice were used to construct in vitro and in vivo models, respectively. Through A series of experiments such as qRT-PCR, Western blot, CCK-8, flow cytometry, dual-luciferase reporter experiment, HE staining and TUNEL staining, the role of circ_0008285 in sepsis-induced ALI was explored. In LPS-induced RAW264.7 cell, circ_0008285 and MAPK14 were over-expressed, but miR-375 was low-expressed compared with control. The levels of IL-1β, IL-6, TNF-α, iNOS and CD86 were reduced, but CD206 and Arg1 expression were enhanced both in vitro and in vivo after knockdown of circ_0008285. In TC-1 cell co-cultured with LPS+sh-circ_0008285 cells, the viability was increased and the apoptosis level was decreased compared with LPS+sh-NC. Circ_0008285 was the sponge of miR-375, and MAPK14 was the downstream target of miR-375. The injury score, W/D ratio, MPO level and apoptosis level in lung tissue were decreased after knockdown of circ_0008285. Moreover, the total protein, neutrophils and macrophages in BALF were increased. Collectively, this study identified that circ_0008285 could sponge miR-375 to influence MAPK14 expression, and then regulate macrophage polarization of sepsis-induced ALI, which provided new insights for the treatment of sepsis-induced ALI.

Vascular calcification is a critical pathological hallmark of cardiovascular diseases. Although previous studies have indicated that M1 macrophages significantly promote calcification, the exact underlying mechanisms remain unclear. This study examined whether semaphorin 4D (Sema4D), a class IV semaphorin involved in atherosclerosis development, is secreted by M1 macrophages and contributes to the calcification of vascular smooth muscle cells (VSMCs). We observed elevated expression and secretion of Sema4D in both M1 and M2 macrophages, with significantly higher levels in M1-polarized cells. M1 macrophages promoted VSMC calcification in both co-culture and conditioned medium systems, as evidenced by increased alkaline phosphatase activity, enhanced calcium deposition, and upregulation of osteogenic markers. Notably, neutralization of Sema4D in M1 conditioned medium using pepinemab, an anti-Sema4D antibody, effectively attenuated VSMC calcification induced by M1 macrophages. Conversely, supplementation of conditioned medium with recombinant Sema4D enhanced calcification and osteogenic signaling in VSMCs, further supporting the pro-calcifying role of Sema4D. Collectively, these findings highlight macrophage-derived Sema4D as a pivotal regulator of vascular calcification and a promising therapeutic target.

Lung cancer exhibits high mortality and incidence rates, with tumor-associated macrophages (TAMs) serving as critical contributors to cancer progression. This study investigates the unexplored mechanistic role of HRD1-an E3 ubiquitin ligase implicated in cancer - in orchestrating TAM polarization to affect lung cancer pathogenesis.

HRD1 expression in lung cancer using TCGA database and validated its impact via IHC. THP-1 cells and macrophages isolated from murine tumor tissues via magnetic bead sorting were transfected with the oe-HRD1 plasmid, followed by flow cytometry, ELISA, and RT-qPCR assays to investigate HRD1's regulatory effects on macrophage polarization and function. Co-IP was employed to investigate interactions between USP7 and HRD1/PD-L1, while Immunofluorescence elucidated underlying mechanisms.

HRD1 was highly expressed in lung cancer and promotes tumor growth in tumor-bearing mice and proliferation in THP-1 cells. Strikingly, both in vivo and in vitro overexpression of HRD1 drove macrophage M2 polarization. Mechanistically, USP7 interacted independently with HRD1 and PD-L1, while HRD1 binding to USP7 facilitated PD-L1 ubiquitination. Furthermore, HRD1 overexpression upregulated USP7 expression, thereby enhancing M2 polarization.

HRD1 promotes lung cancer progression by regulating TAM M2 polarization via USP7, offering novel therapeutic targets and diagnostic perspectives for early-stage lung cancer intervention.

In recent years, the gut microbiome has been recognized as one influential factor in cancer development. Particularly in colorectal cancer (CRC), several studies observed a major imbalance of the intestinal microbiota, marked by a reduction in beneficial bacterial species, such as Roseburia intestinalis, and an increase in opportunistic pathobionts, like Peptostreptococcus stomatis. We previously observed that specific Eubacteriales, including R. intestinalis, were significantly reduced in CRC patients and have a potent anti-tumor immune effect when applied as oral monotherapy in mice. Here, we investigate the molecular mechanism of R. intestinalis on various cell types in vitro, highlighting its potential therapeutic value in CRC. Co-culture experiments with macrophages demonstrated that R. intestinalis exposure induced an increase in the M1 phenotype and decreased the M2 phenotype, suggesting macrophage-polarizing properties of these bacteria. R. intestinalis also triggered a gene expression profile resembling M1 macrophages and led to distinct chemokine and cytokine secretion in cancer cells, suggesting an immune-activating environment. However, we did not observe direct cytotoxic effects in cancer cells. Our research provides insights into the potential of R. intestinalis to activate immune responses, supporting further investigation into its therapeutic role in CRC. These findings underscore the need for deeper studies on the bacterium's impact on CRC pathogenesis and treatment.

Therapeutic mRNA vaccines are limited in inducing tumor shrinkage in advanced cancers due to their inability to overcome immune-suppressive mechanisms within tumors. In this study, we developed an HPV-immunogen-expressing oncolytic virus (OV) using HSV-1 for HPV-related cancer treatment. A mouse syngeneic tumor model evaluates the effectiveness of intratumoral OV application for E6+E7+ tumors. Comparative analysis of OV and mRNA vaccines reveals distinct mechanisms in tumor treatment. Single-cell RNA sequencing and flow cytometry show that OV enhances cytotoxic T cell infiltration, polarizes neutrophils and macrophages toward anti-tumor phenotypes, and promotes immune activation within the tumor. In contrast, the mRNA vaccine more effectively activates peripheral antigen-specific T cell responses. A heterologous prime-boost strategy using the mRNA vaccine to prime systemic T cells, followed by OV therapy to direct these cells into the tumor, leads to significant tumor regression. This combination optimizes both systemic and intratumoral immune responses for advanced HPV-related cancers.

The incidence of allergic diseases has been increasing annually, severely affecting the quality of life of patients. With the growing recognition of traditional medicine, acupuncture, an ancient Chinese therapeutic method, has gradually gained attention for its potential in immune modulation. Studies have shown that macrophages play a crucial role in the development of allergic diseases, and acupuncture may influence allergic reactions by modulating the function of macrophages. This article aims to systematically evaluate the regulatory effects of acupuncture on macrophages in allergic diseases and the corresponding mechanisms. It analyzes existing research findings and explores the clinical application prospects of acupuncture in this context. By understanding how acupuncture affects the activation, secretion, and role of macrophages in immune responses, we hope to provide new insights and directions for the treatment of allergic diseases.

The enhanced M1 macrophage activation and proportion significantly promote the progression of renal fibrosis in the unilateral ureteral obstruction (UUO) model, while the underlying mechanisms need to be further studied. Here, we examined whether or not endoplasmic reticulum (ER) stress contributed to M1 macrophage activation and the mechanisms in this process. In the UUO mouse model, the proportion of M1 macrophages could be significantly increased in the early renal fibrosis, with the ER stress activated. The inhibitor of ER stress (4-PBA) significantly suppressed the activation of M1 macrophages and alleviated the renal fibrosis in the UUO mouse model. Furthermore, the renal fibrosis could be relieved after the administration of IRE1α inhibitor (4μ8C), with the downregulation of ER stress and M1 macrophage activation. Mechanistically, ER stress-enhanced activation of M1 macrophages was regulated through the IRE1α/XBP1s-p38 MAPK pathway. IRE1α-deficient macrophages could alleviate the renal fibrosis in the UUO mouse model. Thus, our findings suggest that the ER stress pathway regulates M1 macrophage activation in the UUO model, which provides a novel therapeutic approach for renal fibrosis.

Acute Lung Injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are major threats to human health, characterized by high mortality rates and a lack of effective treatments. Given the significant role of an over-activated inflammatory response and macrophage polarization in the development of ALI, and the unknown effect of vitamin E in this context, our study aimed to explore vitamin E's potential in alleviating ALI. We established an ALI mouse model by intratracheal instillation of LPS and isolated BMDMs for in-vitro experiments. Results indicated that vitamin E treatment significantly reduced LPS-induced lung injury, as shown by decreased lung wet/dry weight ratio, lower levels of pro-inflammatory factors in bronchoalveolar lavage fluid, and improved mouse survival rates. Vitamin E also alleviated oxidative stress by modulating oxidative and reducing products. Mechanistically, it activated the AMPK signal, upregulated NRF2, scavenged reactive oxygen species, inhibited the NF-κB signal pathway, and regulated macrophage polarization towards the anti-inflammatory M2 phenotype while suppressing the pro-inflammatory M1 polarization. In conclusion, vitamin E may serve as a potential adjuvant treatment for ALI through the AMPK/NRF2 signaling axis, although further research on optimal dosage and combination therapies is needed.

Milk-derived extracellular vesicles (MEV) have received increasing attention due to their physiological benefits for newborn growth and development. However, their physiological characteristics and immunomodulatory capacities during lactation remain unclear. In this study, we isolated MEV from porcine milk at day 1, week 1, week 2, and week 3 after parturition and compared their differences by common EV characterization, showing the higher concentration and smaller mean size of MEV from colostrum. Porcine MEV could be internalized by RAW264.7 macrophages and functionally deliver immune-related microRNAs (miRNAs). Furthermore, MEV promoted macrophage polarization toward the M2-like phenotype and exerted anti-inflammatory effects in vitro. Mice models with sepsis also displayed that MEV suppressed the secretion of pro-inflammatory cytokines in serum and drove an anti-inflammatory M2-like phenotype of the spleen, ultimately weakening immune responses. Especially, MEV from colostrum exhibited the most robust effects on immunoregulation. Overall, this study provides valuable information for MEV secretion patterns and their differences in immunomodulatory bioactivities.

The pathogenesis of chronic subdural hematoma (CSDH) has traditionally been associated with inflammation, but the efficacy of anti-inflammatory drug therapy is limited. Recent literatures suggest that immune dysregulation rather than sole inflammation, plays a vital role in the development of CSDH. In this study, the dynamics of macrophage polarization were explored to elucidate changes in immune status during CSDH evolution. Nakaguchi computerized tomography (CT) classification method was employed to categorize CSDH into four types, including homogeneous, laminar, separated and trabecular subtypes. Samples from the hematoma cavity were collected. The percentages of M1 and M2 macrophages and the M1/M2 proportion were determined by flow cytometry. The M1-related inflammatory (IL-1β, IL-6, IL-12, and TNF-α) and M2-related anti-inflammatory factors (IL-4, IL-10, IL-13, and TGF-β) were measured by ELISA. The relationship among CT subtypes, macrophage polarization and recurrence were evaluated by univariate and multivariate logistic regression analyses. A nomogram was established to score significant factors, and the bootstrap method was used for internal validation to calculate the concordance index (C-index) and generating calibration plots. A total of 127 patients with CSDH were included, among which 28 cases (22.04%) experienced recurrence within three months post-surgery. Significant differences were found in the percentages of M1 and M2 macrophages, the M1/M2 ratio, and related cytokines among different subtypes in CT classifications (P < 0.001). As CSDH evolved according to different CT subtypes, M1 macrophages gradually decreased, while M2 macrophages significantly increased, accompanied by a downregulation of the M1/M2 ratio. The similar changes were found in M1-related inflammatory cytokines (IL-1β, IL-6, IL-12, and TNF-α) and M2-related anti-inflammatory cytokines. Additionally, compared to the non-recurrence group, the recurrence group had higher percentages of M1 and M1/M2 ratio, but lower percentages of M2 (P < 0.05). LASSO regression analysis identified the dichotomized Nakaguchi CT classification, degree of brain atrophy, postoperative drainage volume, and hematoma volume were independent risk factors of recurrence (P < 0.05). Based on this, the established nomogram prediction model showed an AUC of 0.898, indicating good predictive efficacy and accuracy. The study demonstrated that the immune status within the hematoma cavity shifts from an inflammatory to an anti-inflammatory state during CSDH progression. Furthermore, it was found that altered immune balance gives rise to CSDH evolution and recurrence following surgery instead of inflammation itself.

Osteoarthritis (OA) is a common joint disorder that causes significant disability. Previous studies suggested that the predominance of M1 macrophages (MΦs) exacerbates inflammation and cartilage degradation in OA, suggesting that shifting the polarization toward M2 MΦs could be a promising therapeutic strategy. We recently developed CRISPRa-engineered macrophages, termed Elite MΦs, that express IL-10 and maintain a stable M2 phenotype. However, achieving effective and sustained delivery of these cells to the OA joint remains a challenge. In this study, we synthesized two injectable aldehyde hyaluronic acid-based hydrogels, CHO/CDH and ACHO/CDH hydrogels, to serve as Elite MΦ delivery platforms. Comprehensive analyses identified the ACHO/CDH hydrogel as superior due to its enhanced suitability for encapsulating and delivering Elite MΦs. When loaded with Elite MΦs, the ACHO/CDH hydrogel was able to not only localize Elite MΦs but also enhance their anti-inflammatory and reparative effects. Furthermore, intra-articular injection of the Elite MΦ-loaded ACHO/CDH hydrogel in an OA mouse model resulted in notable improvements in the joint's cellular environment, alleviating cartilage degradation and synovial inflammation. These results highlight the ability of the ACHO/CDH hydrogel to rebalance the inflammatory imbalance and promote cartilage repair. This approach not only targets the underlying inflammatory processes more directly than traditional therapies but also harnesses the regenerative potential of macrophages, offering a transformative strategy for OA management.

Facial nerve injury (FNI), hindered by hypoxic microenvironments limiting Schwann cell (SCs) repair potential, remains a therapeutic challenge. We developed light-responsive Chlorella hydrogels (C-Gel) to modulate oxygen release and inflammation. In vitro, light-activated C-Gel enhanced RSC96 SC proliferation, migration, and secretion while reducing reactive oxygen species (ROS), hypoxia-inducible factor-1α (HIF-1α), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). It also shifted macrophage polarization from pro-inflammatory M1 (inducible nitric oxide synthase (iNOS)+/TNF-α+) to anti-inflammatory M2 (arginase-1 (Arg-1)+/IL-10+), with M2-conditioned mediumboosting SCs production of neurotrophic factors (nerve growth factor, NGF; glial cell line-derived neurotrophic factor, GDNF), adhesion molecules (neural cell adhesion molecule-1, NCAM-1), regeneration-associated proteins (c-JUN), and myelin components (myelin basic protein, MBP; myelin-associated glycoprotein, MAG). In vivo, C-Gel-light therapy improved behavioral recovery in FNI rats, suppressed inflammation (ROS/HIF-1α/TNF-α), and enhanced SC-mediated remyelination (S100 calcium-binding protein, S100; neurofilament 200, NF200). RNA sequencing identified upregulated phosphoinositide 3-kinase-protein kinase (PI3K-Akt) and calcium ion (Ca²+) signaling pathways. This oxygen-regulating, immunomodulatory biomaterial offers a dual-action strategy to advance FNI rehabilitation by synergistically optimizing the regenerative microenvironment.

Asthma 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.

M2Φ-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.

M2Φ-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.

These 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.

Sepsis is a life-threatening multiple organ dysfunction resulting from a dysregulated host response to infection, and patients with sepsis always exhibit a state of immune disorder characterized by both overwhelming inflammation and immunosuppression. The aging of immune system, namely "immunosenescence", has been reported to be correlated with high morbidity and mortality in elderly patients with sepsis. Initially, immunosenescence was considered as a range of age-related alterations in the immune system. However, increasing evidence has proven that persistent inflammation or even a short-term inflammatory challenge during sepsis could trigger accelerated aging of immune cells, which might further exacerbate inflammatory cytokine storm and promote the shift towards immunosuppression. Thus, premature immunosenescence is found in young sepsis individuals, which further aggravates immune disorders and induces the progression of sepsis. Furthermore, in old sepsis patients, the synergistic effects of both sepsis and aging may cause immunosenescence-associated alterations more significantly, resulting in more severe immune dysfunction and a worse prognosis. Therefore, it is necessary to explore the potential therapeutic strategies targeting immunosenescence during sepsis.

KLF15 is involved in cardiovascular disease processes by regulating vascular remodeling and metabolic disorders. Macrophages mediate the inflammatory response in deep vein thrombosis (DVT) by secreting inflammatory cytokines and modulating the fibrinolytic system. Therefore, this study aims to discuss the effect of KLF15 on macrophage polarization in DVT.

In vivo, a DVT animal model was used to assess KLF15 expression and macrophage polarization. In vitro, PMA-treated THP-1 cells with KLF15 overexpression were differentiated into M1- and M2-like macrophages, with polarization markers analyzed by molecular and cellular assays.

In vivo experiments, levels of KLF15, iNOS, CD206, IL-1β, IL-6, IL-10 and TGF-β were increased in the DVT animal model. In vitro experiments, KLF15 overexpression augmented iNOS, CD86, IL-12, TNF-α, IL-1β, and IL-6 levels in M1-like macrophages. Additionally, KLF15 overexpression diminished CD206, IL-10, ARG1, IL-10 and TGF-β levels in M2-like macrophages. In CUT&Tag, peaks bound to KLF15 and lgG were mainly located in the promoter and intronic regions, and KLF15 protein bound more peaks than lgG near the TSS site. YY1, EIF4E, LCK, HMGB1, GPD2, MORF4L1, HIPK2 and NEK2 were hub genes in the peaks that bind to KLF15. ChIP assay confirmed that KLF15 bound the NEK2 promoter in M1-like macrophages and enhanced its transcription and NF-κB pathway activity.

KLF15 facilitates M1 macrophage polarization in DVT via the NEK2/NF-κB pathway, highlighting its potential as a therapeutic target for DVT management. Future studies are warranted to explore its clinical applicability and mechanistic nuances.

The tumor microenvironment (TME) impedes the effectiveness of therapeutic strategies such as chemodynamic therapy (CDT). This study presents a novel nanoscale drug delivery system designed for the precise release of the chemotherapeutic agent doxorubicin (DOX), aiming to overcome treatment limitations, reduce systemic toxicity, and enhance antitumor efficacy. Mn(III) serves as an immunomodulatory agent, while Cu(II) regulates the levels of glutathione (GSH). Layered double hydroxides (LDHs) were synthesized and efficiently loaded with DOX, followed by surface modification with hyaluronic acid (HA). The HA-coated LDH/DOX nanocarriers showed effective internalization by tumor cells and provided a pH-responsive release of DOX. In vitro, the LDH/HA/DOX complex exhibited strong catalytic activity in the Fenton reaction. In vivo studies using an H22 hepatocarcinoma model confirmed its potent antitumor activity and excellent biocompatibility. Immunohistochemical analyses revealed that treatment with LDH/HA/DOX significantly increased infiltration of M1-polarized tumor-associated macrophages (TAMs), CD4 + T cells and CD8 + T cells, while decreasing M2-polarized TAMs. This change in immune cell profile was associated with notable tumor growth inhibition.

Migrasomes are newly discovered extracellular organelles released by migrating cells, such as immune cells, tumor cells, and other special functional cells like podocytes and embryonic cells. They contain a diverse array of constituents, including proteins, lipids, and RNA which can be released to the designated location to activate surrounding cells, thereby facilitating intercellular communication and signal transduction. Since then, our understanding of the mechanism and function of the migrasomes has expanded exponentially, with recent evidence indicating they are involved in various physiological and pathological processes, particularly in immune regulation. Furthermore, methods and techniques for extracting, detecting, and characterizing migrasomes are constantly advancing. Herein, we summarize the current understanding of migrasomes and their key roles in modulating immune responses, as well as the prospective challenges surrounding their clinical application, aiming to provide novel insights into the emerging organelles.

Brain metastasis (BM) is the most common and serious complication of breast cancer (BC). There is significant interest in investigating the crosstalk between BC cells and immune cells. β-elemene is the main pharmacodynamic component of Curcumae Rhizoma, a traditional Chinese medicine that is commonly used for the clinical treatment and prevention of various tumors. However, the specific underlying mechanism of β-elemene in BC-BM is still unclear.

An intracardiac (ICT) injection model was used to establish specific BC-BM cells, then an intracarotid (ICD) injection model was used to verify the inhibitory effect of β-elemene in BC-BM. Tumor-cell-conditioned media, a primary microglia co-culture model, and an in vitro recruitment experiment were used to explore crosstalk between BC cells and immune cells. TMT-based quantitative proteomic, ELISA, IF, and other molecular biotechnologies were used to investigate the mechanisms.

The BC-BM cells established in our study not only increased BM rates but also exhibit mesenchymal phenotype and activated the JAK-STAT signaling pathway. Microglia, particularly M2 microglia, were enriched in BM lesions and secreted high levels of both IL6 and CCL2. Hypersecretory IL6 reversed the MET process of BC cells by regulating the JAK2/STAT3 signaling pathway to promote colonization in the brain. Increased levels of CCL2 significantly recruited monocytic myeloid-derived suppressor cells (M-MDSCs) to induce an immunosuppressive brain microenvironment. β-elemene could significantly inhibit BC-BM in mice by regulating the IL6/STAT3 signaling pathway and suppressing the M-MDSC recruitment.

Our work first demonstrated that β-elemene regulated the IL6/STAT3 axis and M-MDSC recruitment to reconstruct immunosuppressive brain microenvironment to suppress BC-BM.