Rheumatoid arthritis (RA) is a chronic autoimmune disease. Hypochlorous acid (HClO) is a signature reactive oxygen species (ROS) closely associated with the progression of RA. Here, we report a novel fluorescent probe, ZCP1, which exhibits high sensitivity to HClO. In the presence of HClO, ZCP1 demonstrates a rapid detection time of 20 s and a low detection limit of 19.1 nM, allowing for fast and sensitive reactions with HClO, with a 150-fold fluorescence enhancement. ZCP1 can be employed for fluorescent detection of both exogenous and endogenous HClO levels in live cells. Furthermore, ZCP1 has been utilized to detect endogenous HClO in a mouse model of RA. This work provides a reliable tool for monitoring endogenous HClO both in vivo and in vitro, offering significant potential for future biological and pathological studies related to HClO.

Cutaneous manifestations are the most common presenting sign of chronic graft-versus-host disease (GVHD), and the extent of cutaneous involvement is also highly correlated with prognosis. Very little is understood about the underlying pathogenesis underpinning injury at this location, especially the contribution of keratinocytes and other structural skin cells. We performed single-cell RNA sequencing to compare the transcriptome of epidermal and dermal chronic GVHD samples with that of healthy control samples. Our findings reveal unique nonimmunologic and immunologic changes in epidermal keratinocytes and dermal immune cells. Specifically, we observed upregulation of alarmins and inflammatory cytokines and downregulation of anti-reduction-oxidation and activator protein-1 pathway genes in the keratinocyte compartments. In dermal immune cell subsets, we showed increased CD8+ T, CD4+ T, CD4+Foxp3+ regulatory T, and NK cells in chronic GVHD, accompanied by increased signals of leukocyte functions, inflammatory responses, cytolysis, and macrophage M1 polarization. Finally, we also delineated the donor versus recipient cellular origin of nonimmune and immune cell populations in sex-mismatched chronic GVHD. Taken together, these data reveal complex keratinocyte and immune responses in cutaneous chronic GVHD, supporting future studies of skin cell contributions to pathogenesis and potential local treatment strategies.

High body mass index (BMI), encompassing overweight and obesity, is a well-established risk factor for developing breast cancer (BC). The underlying mechanisms linking elevated BMI to increased BC risk involve metabolic reprogramming and chronic inflammatory microenvironments regulated by cellular networks within breast white adipose tissue (WAT). However, the complicated landscape and specific cell chat leading to BC-related adipose microenvironment remained unclear.

We unveiled a comprehensive cell atlas by employing single-cell (N = 27) and single-nuclei (N = 6) transcriptomics to address dynamic changes of immune and stromal cell components within WAT in high BMI population. Bulk RNA-seq data sets were used for validation.

Characteristics of adipose-infiltrating tissue-resident macrophages (PVMs), APOD+γδ T cells, and mature FKBP5+ adipocytes in breast cancer women with high BMI were revealed, in terms of transcriptional genes, metabolism features, developmental trajectories and gene set enrichment analysis (GSEA). PVMs upregulated c-Maf combined with its co-activator CREB1 to increase TCA cycles. APOD+γδ T cells were found to elevate intracellular lipid metabolism, leading to poor clinical prognosis. Mature FKBP5+adipocytes served as an advanced adipogenesis mediator to promote tumor aggressiveness. In-depth analysis of cell-cell interactions uncovered a remodeling trend towards metabolic dysfunction and chronic inflammation in WAT with weight gain via EGF, CXCL, and CCL signalings.

These results provided a novel understanding of detailed and unbiased cellular landscape of WAT in breast cancer with high BMI from single-cell atlas perspective, uncovering interplays between breast adipose-infiltrating immune cells and stromal cells that promote progression of BC under high BMI conditions.

Osteoarthritis (OA) is a degenerative joint disease, often accompanied by inflammation. It has reported that low-dose radiotherapy (LDRT) has anti-inflammatory effect for benign pathologies and has been used for clinical treatment of OA in some European regions. However, the underlying molecular mechanisms of LDRT alleviating OA are only poorly understood. Herein, it is verified that LDRT improved the locomotor ability of OA rats, increased the locomotor distance and speed in the in vivo experiments. Moreover, LDRT decreased the degree of cartilage damage, attenuated the synovial inflammation, and promoted macrophage polarization towards M2 type. For the in vitro experiments, LDRT promoted macrophage polarization towards M2-type, which enhanced cell growth and adjusted the inflammatory factors in chondrocyte. Additionally, it is found LDRT could ameliorate OA pain through inhibiting spinal cord inflammation. Take together, our study suggests that LDRT could ameliorate OA symptoms and relieve OA-related pain by exerting its anti-inflammatory effect.

Macrophage polarization, switching between pro-inflammatory M1 and anti-inflammatory M2 states, is crucial for disease dynamics in inflammatory, metabolic, and cancer contexts. Modulating this polarization is a clinical challenge, but natural alkaloids, with their potent anti-inflammatory and immunomodulatory effects, show promise in reprogramming macrophage phenotypes.

This review explores the applications of natural alkaloids-such as matrine, berberine, koumine, sophoridine, and curcumin-in modulating macrophage polarization. It aims to highlight their potential in reprogramming macrophage phenotypes and improving therapeutic outcomes across various diseases.

A comprehensive literature review was conducted using databases like PubMed, Web of Science, Science Direct and Google Scholar, employing targeted keywords related to natural alkaloids, macrophage polarization, and disease treatment. The analysis primarily focused on articles published between 2020 and 2024.

This review summarizes how natural alkaloids regulate macrophage polarization, promoting the M2 phenotype to reduce inflammation, thereby playing a therapeutic role in anti-inflammatory, cardiovascular, and metabolic diseases. At the same time, they also promote M1 polarization to inhibit tumor development.

Accumulating evidence demonstrates that macrophage polarization regulation by natural alkaloids holds notable clinical value for disease intervention. They alleviate inflammation, enhance antitumor immunity, and improve treatment outcomes, demonstrating their importance in innovative therapeutic strategies. Moreover, combining alkaloids with immunotherapy enhances treatment efficacy, further highlighting their versatility in a variety of therapeutic applications.

Inflammatory bowel disease (IBD) is a chronic inflammatory bowel disease with unclear causes and limited treatment options. Sodium butyrate (NaB), a byproduct of dietary fiber in the intestine, has demonstrated efficacy in treating inflammation. However, the precise anti-inflammatory mechanisms of NaB in colon inflammation remain largely unexplored. This study aims to investigate the effects of NaB on dextran sulfate sodium (DSS)-induced colitis in rats. The findings indicate that oral administration of NaB effectively prevent colitis and reduce levels of serum or colon inflammatory factors. Additionally, NaB demonstrated in vitro inhibition of RAW264.7 inflammation cytokines induced by LPS, along with suppression of the ERK and NF-κB signaling pathway activation. Moreover, NaB mitigated LPS and Nigericin-induced RAW264.7 pyroptosis by reducing indicators of mitochondrial damage, including increased mitochondrial membrane potential (JC-1) levels and decreased Mito-ROS production. NaB increases ZO-1 and Occludin expression in CaCo2 cells by inhibiting RAW264.7 pyroptosis. These results suggest that NaB could be utilized as a therapeutic agent or dietary supplement to alleviate colitis.

Endogenous bioelectrical signals are quite crucial in biological development, governing processes such as regeneration and disease progression. Exogenous stimulation, which mimics endogenous bioelectrical signals, has demonstrated significant potential to modulate complex biological processes. Consequently, increasing scientific efforts have focused on developing methods to generate exogenous electrons for biological applications, primarily relying on piezoelectric, acoustoelectric, optoelectronic, magnetoelectric, and thermoelectric principles. Given the expanding body of literature on this topic, a systematic and comprehensive review is essential to foster a deeper understanding and facilitate clinical applications of these techniques. This review synthesizes and compares these methods for generating exogenous electrical signals, their underlying principles (e.g., semiconductor deformation, photoexcitation, vibration and relaxation, and charge separation), biological mechanisms, potential clinical applications, and device designs, highlighting their advantages and limitations. By offering a comprehensive perspective on the critical role of exogenous electrons in biological systems, elucidating the principles of various electron-generation techniques, and exploring possible pathways for developing medical devices utilizing exogenous electrons, this review aims to advance the field and support therapeutic innovation.

Stromal cells are critical regulators of hematopoietic stem/progenitor cells and skeletal homeostasis. Although precise systems for functional analysis are critical to investigate mechanistically bone and bone marrow (BM)-derived stromal cells, the establishment of reproducible, highly enriched ex vivo methods for stromal cell isolation, culture and evaluation have been challenging, leading to inconsistent data on stromal cell function. In this work, we carefully tested ex vivo culture of murine stromal cells from BM and bone and discovered abundant and persistent contamination of monocytes and macrophages. We succeeded in establishing highly enriched ex vivo culture system for stromal cells by eliminating persistent monocytes and macrophages using selection against the immunological markers F4/80, Ly6C, and CD45. Transcriptional and functional assays of enriched stromal cell culture revealed differential characteristics of stromal cells from different origins, a dormant signature for bone-derived cells and a highly proliferative progenitor-like signature for BM-derived cells. Monocyte and macrophage contamination reduced signatures of immature stromal cells such as expression levels of SOX9 and CD140a as well as the cells' ability to support hematopoietic stem and progenitor cells based on our growth factor-free co-culture system of hematopoietic cells and stromal cells followed by in vivo functional assays. The inhibitory effects of macrophages on stromal cells may be explained by their potent production of inflammatory cytokines such as CXCL2, CCL3, and complement factor (C1q) confirmed by protein immunoassay of culture supernatant, as well as the differential contribution of pre-osteoblasts to the stromal cell population. This study highlights the functional diversity of stromal cells depending on the microenvironment of origin while addressing a critical limitation of murine ex vivo systems. Our robust culture system enables the study of isolated stromal cells function as well as the impact of stromal cells-macrophage crosstalk.

Hepatocellular carcinoma (HCC) represents a multifaceted and aggressive cancer frequently associated with chronic inflammation and immune cell activation. The pathogenesis of HCC is influenced by a variety of factors such as long non-coding RNAs (lncRNAs). LncRNAs, a significant class of non-coding RNAs, contribute to the intricate nature of the transcriptome and are extensively distributed across various tissues and cell types in mammals. In HCC, these transcripts are crucial not only for deepening our molecular understanding but also for advancing clinical outcomes, as they serve as both oncogenes and tumor suppressors by dysregulating essential genes and signaling pathways. Additionally, macrophage polarization is crucial in HCC tumor progression. The study explores the role of lncRNAs in hepatocellular carcinoma (HCC) and elucidates the specific molecular mechanisms by which key lncRNAs such as HULC and MALAT1 regulate macrophage polarization in the tumor microenvironment. These lncRNAs modulate cytokine profiles and influence immune regulators including IL-10 and TGF-β, steering macrophages toward an M2-like, pro-tumor phenotype that fosters aggressive tumor characteristics and progression. Mechanistically, these transcripts interact with epigenetic modifiers like EZH2 to alter histone modifications and chromatin accessibility, while also stabilizing mRNAs that encode inflammatory mediators, thereby reinforcing an immunosuppressive response. The clinical implications of these findings are substantial. The detection of such lncRNAs in patient samples offers a minimally invasive diagnostic avenue, while their pivotal role in complex immune cell behavior positions them as promising prognostic biomarkers. Moreover, targeting these lncRNAs may lead to innovative therapeutic strategies aimed at disrupting tumor-supportive inflammatory cascades and restoring an effective antitumor immune response. Understanding the intricate interplay between lncRNA-mediated epigenetic regulation and macrophage polarization not only refines our grasp of HCC progression but also opens new pathways for interventions designed to improve patient outcomes.

The radiation-induced abscopal effect (RIAE) can suppress distal metastatic lesions and elicit a systemic anti-tumor response; however, the underlying mechanisms remain to be fully elucidated. Current research has shown that autophagy promotes the production of IFN-β by regulating mitochondrial DNA (mtDNA), thereby contributing to the modulation of RIAE. Nevertheless, the downstream pathways through which IFN-β influences RIAE require further investigation. In this study, we observed accumulation of an abundance of mtDNA in the cytosol of mammary tumor cells following RT, along with the presence of mitochondrial RNA (mtRNA). These molecules activated the cGAS-STING and RIG-I-MAVS signaling pathways, respectively, thereby synergistically promoting the production of IFN-β and secretion into the extracellular matrix. Subsequently, IFN-β facilitated the polarization of macrophages in distant non-irradiated tumor microenvironment towards the M1 phenotype through activating STAT1. Furthermore, our findings indicate that high linear energy transfer (LET) carbon ions are significantly more effective in inducing the production of IFN-β and promoting macrophage polarization compared to low-LET X-rays. Thus, our findings provide insights into the intricate mechanisms by which mtDNA/RNA and IFN-β mediate RIAE, suggesting that IFN-β could be a promising target for provoking RT immunogenicity in patients with breast cancer and high-LET radiation might effectively elicit RIAE.

Self-assembling peptides (SAPs) are fully defined nanobiomaterials offering unprecedented opportunities to control nanostructure and chemical attributes to investigate and manipulate cellular signals. To investigate the influence of chemical and morphological characteristics on inflammatory signaling in native immunity, we designed five β-sheet SAPs: EFEFKFEFK (EF8), YEFEFKFEFK (YEF8), EFEFKFEFKY (EF8Y), YEFEFKFEFKY (YEF8Y), and EYEFKFEFK (EYF8) (F: phenylalanine; E: glutamic acid; K: lysine, Y: tyrosine). The position of tyrosine in the peptide sequence dictated the self-assembly into nanostructures, with all SAPs self-assembling into thin constituent nanofibers with d ≈ 3.8 ± 0.4 nm, and sequences YEF8 and EF8 showing a propensity for associative bundling. These distinct SAPs induced contrasting inflammatory responses of monocytic model THP-1 cells-derived macrophages (MΦs). Presence of soluble EF8 nanofibers (at 2 mM) induced an anti-inflammatory response and polarization toward an M2 state, whereas YEF8 (at 2 mM) displayed a tendency for inducing a pro-inflammatory response and polarization toward an M1 state. EF8Y, YEF8Y, and EYF8 SAPs did not induce an inflammatory response in our models. These results were validated using peripheral blood mononuclear cells (PBMCs)-derived MΦs from human donors, confirming the critical role of EF8 and YEF8 SAPs as possible orchestrators of the repair of tissues or inducers of pro-inflammatory state, respectively. The same MΦs polarization responses from THP-1-derived MΦs cultured on 20 mM hydrogels were obtained. These findings will facilitate the utilization of this family of SAPs as immunomodulatory nanobiomaterials potentially changing the course of inflammation during the progression of various diseases.

Interleukin-22 (IL-22), a cytokine from the IL-10 family produced by T cells and innate lymphoid cells, plays a crucial role in immune responses and tissue regeneration. Its association with liver disease has garnered significant attention; however, its exact impact remains controversial. This review aims to enhance the current understanding of the dual role of IL-22 in liver disease by exploring its protective and pathogenic effects. First, we provide an overview of IL-22 biology, including its source, receptors, and signaling pathways. Subsequently, we offer a comprehensive overview of the dual function of IL-22 in non-neoplastic liver disease, emphasizing its antiapoptotic and regenerative properties. We also discuss the applicability of the conclusions drawn from studies on nonalcoholic fatty liver disease to metabolic dysfunction-associated steatotic liver disease. Furthermore, we elaborate on the intricate role of IL-22 in hepatocellular carcinoma, particularly its influence on the tumor microenvironment, proliferation, and immune evasion. In conclusion, IL-22 is paradoxical in liver disease, acting as a friend and foe. It is imperative to understand this paradox to develop targeted therapies that capitalize on the beneficial effects of IL-22 while mitigating its detrimental effects.

The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent wound healing and remodeling. However, understanding about the process is still limited. Macrophages are critically involved in inflammation resolution after MI. Krüppel-like factor 9 (Klf9) is a C2H2 zinc finger-containing transcription factor that has been implicated in glucocorticoid regulation of macrophages. However, the contribution of Klf9 to macrophage phenotype and function in the context of MI remains unclear. Our study revealed that KLF9 deficiency resulted in higher mortality and cardiac rupture rate, as well as a considerable exacerbation in cardiac function. Single-cell RNA sequencing and flow cytometry analyses revealed that, compared with WT mice, Klf9-/- mice displayed excessive neutrophil infiltration, insufficient macrophage infiltration, and a reduced proportion of monocyte-derived CD206+ macrophages after MI. Moreover, the expression of IFN-γ/STAT1 pathway genes in Klf9-/- cardiac macrophages was dysregulated, characterized by insufficient expression at 1 day post-MI and excessive expression at day 3 post-MI. Mechanistically, Klf9 directly binds to the promoters of Stat1 gene, regulating its transcription. Overall, these findings indicate that Klf9 beneficially influences wound healing after MI by modulating macrophage recruitment and differentiation by regulating the IFN-γ/STAT1 signaling pathway.

V-set and immunoglobulin domain containing 4 (VSIG4) is a B7-family-related protein almost exclusively expressed on macrophages. The difference in its expression mediates the dynamic transformation of the polarization state of macrophages, but the underlying mechanism is still unclear. We sought to reveal the correlation between VSIG4 and the polarization of tumour-associated macrophages (TAMs) and the immune escape of tumour cells in colorectal cancer (CRC).

THP-1 monocyte-derived macrophages expressing different levels of VSIG4 were used for in vitro investigations. In addition, the co-culture system was used to verify the effect of tumour cells on the expression of VSIG4 in macrophages, and the effect of VSIG4 expression level on tumour cells in turn. Subcutaneous xenograft models evaluated the tumour growth inhibition efficacy of VSIG4 blockade as monotherapy and combined with immune checkpoint inhibitors (ICIs).

CRC cells secreted lactate to promote VSIG4 expression in macrophages. On the contrary, VSIG4 promoted macrophage M2 polarization and induced malignant progression of tumour cells by promoting M2 macrophage secretion of heparin-bound epidermal growth factor. In vivo experiments confirmed that knockdown VSIG4 inhibited tumour growth and improved the efficacy of ICIs therapy. Mechanistically, lactate secreted by CRC cells promoted its expression by influencing the epigenetic modification of VSIG4 in macrophages. In addition, VSIG4 enhanced the fatty acid oxidation (FAO) of macrophages and upregulated PPAR-γ expression by activating the JAK2/STAT3 pathway, which ultimately induced M2 polarization of macrophages. Downregulation of VSIG4 or blocking of FAO reversed the M2 polarization process of macrophages.

Our findings provide a molecular basis for VSIG4 to influence TAMs polarization by regulating the reprogramming of FAO, suggesting that targeting VSIG4 in macrophages could enhance the ICIs efficacy and represent a new combination therapy strategy for immunotherapy of CRC.

Colorectal cancer cells secrete lactate to upregulate VSIG4 in macrophages via the H3K18la-METTL14-m6A axis. VSIG4 promotes fatty acid oxidation of macrophages and drives its M2-type polarization. These VSIG4-expressing M2 macrophages promote tumour progression and an immunosuppressive microenvironment. Inhibition of VSIG4 expression can synergistically enhance the therapeutic effect of anti-PD-1 antibody.

Septic cardiomyopathy is a frequent complication in patients with sepsis and is associated with a high mortality rate. Given its clinical significance, understanding the precise underlying mechanism is of great value.

Our results unveiled that Z-DNA binding protein 1 (ZBP1) is upregulated in myocardial tissues of lipopolysaccharide (LPS)-treated mice. Single-cell mRNA sequencing (scRNA-seq) and single-nucleus mRNA sequencing (snRNA-seq) indicated that Zbp1 mRNA in endothelial cells, fibroblasts and macrophages appeared to be elevated by LPS, which is partially consistent with the results of immunofluorescence. Through echocardiography, we identified that global deletion of ZBP1 improves cardiac dysfunction and the survival rate of LPS-treated mice. Mechanistically, snRNA-seq showed that ZBP1 is mainly expressed in macrophages and deletion of ZBP1 promotes the macrophage polarisation towards M2-subtype, which reduces inflammatory cell infiltration. Notably, myeloid-specific deficiency of ZBP1 also promotes M2 macrophage polarisation and improves cardiac dysfunction, validating the role of macrophage-derived ZBP1 in septic myocardial dysfunction. Finally, we revealed that LPS increases the transcription and expression of ZBP1 through signal transducer and activator of transcription 1 (STAT1). Fludarabine, the inhibitor of STAT1, could also promote M2 macrophage polarisation and improve cardiac dysfunction of LPS-treated mice.

Our study provides evidence of a novel STAT1-ZBP1 axis in macrophage promoting septic cardiomyopathy, and underscores the potential of macrophage-derived ZBP1 as a therapeutic target for septic cardiomyopathy.

Macrophage-derivedZBP1 exacerbates LPS-induced myocardial dysfunction and inflammatory cellinfiltration. Deletionof ZBP1 promotes macrophage polarisation from M1 to M2. STAT1-ZBP1axis promotes septic cardiomyopathy. ZBP1has emerged as a potential therapeutic target for inflammationand septic cardiomyopathy.

Tissue-resident macrophage (TRM) is crucial for organ development and homeostasis. However, the role of TRM-derived tumor-associated macrophage (TAM) subpopulations in cancer remains unclear. Using single-cell RNA sequencing and lineage tracing, we reported a TRM-derived TAM subpopulation, characterized by VSIG4 overexpression in testicular cancer. Macroscopically, such subpopulation was also found in tumors such as hepatocellular carcinoma, lung cancer, and glioblastoma. It was associated with poor prognosis and the suppression of CD8+ T-cell-dependent immunity via VSIG4. Notably, VSIG4 promoted immunosuppressive effects through direct or indirect modes, including interacting with receptors on CD8+ T cells or inducing transcription of IL-11 in TAMs. More importantly, MEF2C was identified as a key transcription factor that maintained VSIG4 expression and determined the biological behaviors of VSIG4+ TAMs. In preclinical models, targeting VSIG4+ TAMs via VSIG4 or MEF2C demonstrated a favorable effect of enhancing the efficacy of immune checkpoint inhibitors.

Macrophages serve as the primary effector cells in antibacterial immunity in teleost, engaging in both innate and adaptive immune response. However, the specific role of SHP-1, a multi-functional protein tyrosine phosphatase, in teleost macrophages remains elusive. In this study, we first established a cellular immune model using lipopolysaccharide (LPS), a major pathogenic component of Gram-negative bacteria, and then we comprehensively elucidated the function of SHP-1 in primary macrophages derived from Chinese tongue sole. Our results demonstrated that overexpression of SHP-1 inhibited M1 polarization, phagocytosis, respiratory burst of primary macrophages, suppressing the generation of excessive reactive oxygen species (ROS), malondialdehyde (MDA), and proinflammatory cytokines (il-1β, il-6), but increasing the expression of superoxide dismutase (SOD) and anti-inflammatory cytokine (il-10). Whereas SHP-1 silencing (through siRNA or inhibitor) exerted completely opposite effects, further emphasizing its roles as a negative regulator. More in-depth, we revealed that SHP-1 suppressed the activation/transduction of the TLR5-MYD88-NFκB and JAK-STAT3 signal pathways, thereby mitigating the excessive immune reaction in macrophages of Chinese tongue sole. In summary, our findings systematically delineate the functions of SHP-1 and offer mechanistic insights into the management of oxidative stress/inflammation-related diseases, which will contribute to the sustainable development of aquaculture.

Research on the role of macrophages in musculoskeletal (MSK) diseases has significantly increased in recent years. However, a thorough evaluation of the developmental trajectory of this field, including the contributions of prominent authors and primary research themes, remains insufficient. Furthermore, the identification of emerging research hotspots requires more detailed exploration. This study collated articles and reviews addressing "macrophages in MSK diseases" published between 2004 and 2023, with all data extracted from the Web of Science database. The collected data were analyzed using a variety of bibliometric and visualization tools, such as VOSviewer, CiteSpace, GraphPad Prism, and R packages. Results indicate that China and the United States are the leading contributors in this research domain. Among the many academic institutions involved, Shanghai Jiao Tong University and the University of California stand out as the most productive. The journal "Frontiers in Immunology" had the highest publication output on this topic. The five most frequently explored research domains include Immunology, Rheumatology, Pharmacology and Pharmacy, Cell Biology, and Biochemistry and Molecular Biology. These results offer a comprehensive overview of the current state of research in this field and provide meaningful insights for guiding future studies.

Background/Objectives: Periodontitis and diabetes mellitus share a well-established bidirectional relationship, where hyperglycemia exacerbates periodontal inflammation, and periodontal disease further impairs glycemic control. Within the diabetic periodontal microenvironment, an imbalance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages promotes chronic inflammation, oxidative stress, delayed healing, and alveolar bone resorption. Resveratrol (RSV), a polyphenol with antioxidant, anti-inflammatory, and pro-osteogenic properties, holds potential to restore macrophage balance. However, its clinical application is limited by poor bioavailability and instability. This study aimed to develop and evaluate a novel RSV delivery system to overcome these limitations and promote periodontal tissue regeneration under diabetic conditions. Methods: A drug delivery system comprising RSV-loaded solid lipid nanoparticles embedded within a cross-linked hyaluronic acid hydrogel (RSV@CLgel) was formulated. The system was tested under hyperglycemic and inflammatory conditions for its effects on macrophage polarization, cytokine expression, oxidative stress, mitochondrial function, and osteoblast differentiation. Results: RSV@CLgel effectively suppressed pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) while upregulating anti-inflammatory markers (IL-10, TGF-β). It significantly reduced oxidative stress by decreasing ROS and lipid peroxidation levels and improved mitochondrial function and antioxidant enzyme activity. Furthermore, RSV@CLgel enhanced osteoblast differentiation, as evidenced by increased ALP activity, calcium nodule formation, and upregulation of osteogenic genes (COL-I, RUNX2, OCN, OPN). It also inhibited RANKL-induced osteoclastogenesis, contributing to alveolar bone preservation. Conclusions: The RSV@CLgel delivery system presents a promising multifunctional strategy for the management of diabetic periodontitis. By modulating immune responses, reducing oxidative stress, and promoting periodontal tissue regeneration, RSV@CLgel addresses key pathological aspects of diabetes-associated periodontal disease.

Macrophages are pivotal in osteoarthritis (OA) pathogenesis, as their dysregulated polarization can contribute to chronic inflammatory processes. This review explores the molecular and metabolic mechanisms that influence macrophage polarization and identifies potential strategies for OA treatment. Currently, non-surgical treatments for OA focus only on symptom management, and their efficacy is limited; thus, mesenchymal stem/stromal cells (MSCs) have gained attention for their anti-inflammatory and immunomodulatory capabilities. Emerging evidence suggests that small extracellular vesicles (sEVs) derived from MSCs can modulate macrophage function, thus offering potential therapeutic benefits in OA. Additionally, the transfer of mitochondria from MSCs to macrophages has shown promise in enhancing mitochondrial functionality and steering macrophages toward an anti-inflammatory M2-like phenotype. While further research is needed to confirm these findings, MSC-based strategies, including the use of sEVs and mitochondrial transfer, hold great promise for the treatment of OA and other chronic inflammatory diseases.

Background: Tumor-associated macrophages (TAMs) are prevalent in advanced ovarian cancer tissues and ascites, significantly influencing disease prognosis. However, the mechanisms driving TAM polarization and their tumor-promoting effects remain poorly understood. Methods: The subcellular distribution of SNX10 in ovarian cancer tissues was analyzed using single-cell datasets (GSE147082, GSE58937). The Kaplan-Meier Plotter and GEPIA2 databases were used to evaluate SNX10's prognostic relevance. Lentivirus-mediated SNX10 overexpression in THP-1 cells was employed in tumor cell-macrophage co-culture experiments. Transwell assays and flow cytometry assessed SNX10's effects on ovarian cancer cell metastasis and cisplatin-induced apoptosis. RNA sequencing, Western blotting, lysosomal pH detection, lipid droplet staining, and RT-qPCR were performed to explore SNX10's molecular mechanisms in TAM polarization and immune modulation. Results: SNX10 was specifically expressed in TAMs, promoting their polarization into the M2 phenotype. This enhanced the migration and invasion of ovarian cancer cell lines A2780 and A2780/CP70 while reducing cisplatin-induced apoptosis. SNX10 decreased lipid droplet content, downregulated p-mTOR1, and impaired lysosomal function in TAMs. Additionally, SNX10 differentially modulated PD-L1 mRNA expression in platinum-sensitive and platinum-resistant ovarian cancer cells. Conclusions: SNX10 regulates the mTOR1/lysosome pathway in TAMs, influencing lipid metabolism and indirectly modulating ovarian cancer cell metastasis. It also alters PD-L1 mRNA expression, suggesting a role in shaping the tumor immune microenvironment.

Sepsis is a highly dangerous and complex condition that can result in death. It is characterized by a strong reaction to an infection, causing dysfunction in multiple bodily systems and a high risk of mortality. The transformation of macrophages is a vital stage in the procedure as they possess the capability to interchange between two separate types: M1, which promotes inflammation, and M2, which inhibits inflammation. The choice greatly affects the immune response of the host. This analysis underscores the rapidly expanding roles of exosomes and microRNAs (miRNAs) in regulating the trajectory of macrophage polarization during episodes of sepsis. Exosomes, extremely small extracellular vesicles, facilitate cellular communication by transferring biologically active compounds, including miRNAs, proteins, and lipids. We investigate the impact of changes in exosome production and composition caused by sepsis on macrophage polarization and function. Unique microRNAs present in exosomes play a significant role in controlling crucial signaling pathways that govern the phenotype of macrophages. Through thorough examination of recent progress in this area, we clarify the ways in which miRNAs derived from exosomes can either aggravate or alleviate the inflammatory reactions that occur during sepsis. This revelation not only deepens our comprehension of the underlying mechanisms of sepsis, but it also reveals potential new biomarkers and targets for treatment. This assessment aims to amalgamate diverse research investigations and propose potential avenues for future investigations on the influence that exosomes and miRNAs have on macrophage polarization and the body's response to sepsis. These entities are essential for controlling the host's reaction to sepsis and hold important functions in this mechanism.

Acute pancreatitis (AP) is an inflammatory disease that can progress to systemic immune responses and multi-organ damage in its severe forms. Anoectochilus roxburghii (Wall.) Lindl. (AR), a traditional Chinese medicinal plant, has been reported to exhibit anti-inflammatory, hypoglycemic, hepatoprotective, and analgesic properties. Kinsenoside (KD), the primary bioactive glycoside in AR, is responsible for many of its therapeutic effects. Given its anti-inflammatory and immunomodulatory properties, KD may have the potential to mitigate pancreatic inflammation in AP. However, its protective role in AP has not yet been investigated.

This study aimed to investigate the protective effects of the natural active compound KD against acute pancreatitis (AP) and its associated molecular mechanisms.

Two AP mouse models were established: one by intraperitoneal injection of caerulein combined with lipopolysaccharide (LPS) and the other by retrograde injection of sodium taurocholate (NaT) into the biliopancreatic duct. KD (2.5, 5, 10 mg/kg) was administered as a pre-treatment 1 h before the induction of AP. The severity of AP was evaluated through histopathological analysis, while macrophage infiltration and phenotypic changes in pancreatic tissues were examined using immunofluorescence staining and flow cytometry. Bone marrow-derived macrophages (BMDMs) were polarized into the M1 phenotype through two distinct methods: stimulation with LPS and interferon-γ (IFNγ) and indirect co-culture with pancreatic acinar cells. Changes in macrophage phenotype after KD supplementation (100, 200, and 400 μM) were analyzed using quantitative Reverse Transcription PCR (qRT-PCR) and flow cytometry. Network pharmacology and transcriptomic sequencing were utilized to identify potential targets and pathways affected by KD, with validation of key signaling pathways performed through qPCR and Western blot analysis.

In two models of AP mice, KD at a high dose (10 mg/kg) significantly alleviated pancreatic damage. It reduced pancreatic edema, necrosis, and inflammatory cell infiltration, with a notable decrease in macrophage infiltration. Furthermore, KD (10 mg/kg) administration significantly reduced serum lipase by 53.62% in the Caerulein + LPS model and 41.14% in the NaT model, as well as amylase by 28.13% and 27.99%, respectively. Additionally, KD (10 mg/kg) administration mitigated systemic inflammation and lung injury during AP. Both in vivo and in vitro experiments demonstrated that KD (400 μM) significantly reduced the proportion of M1 macrophages. Furthermore, KD (400 μM) downregulated the mRNA expression of M1-associated genes, including Nos2, Tnf, Il1b, and Il6, in macrophages stimulated by both LPS + IFNγ and pancreatic acinar cell-conditioned media. Network pharmacology and transcriptomic analyses identified toll-like receptor 4 (TLR4) as a potential target of KD in the context of AP. KD (400 μM) was shown to inhibit the activation of the TLR4/STAT1 signaling pathway in macrophages exposed to inflammatory stimuli.

KD administration mitigated experimental AP induced by diverse etiologies through the inhibition of M1 macrophage polarization via the TLR4/STAT1 signaling pathway. These findings highlight KD as a promising therapeutic candidate with potential clinical applications in the management of AP.

Suppressing inflammation and promoting intestinal epithelial regeneration are the keys to mucosal healing in individuals with ulcerative colitis (UC). The upregulation of epithelial YAP and the induction of macrophages to polarize to the M2 phenotype in the mucosa can promote intestinal epithelial regeneration and alleviate ulcerative colitis. However, the role of YAP in macrophage polarization remains unclear. Here, we explored the effects of YAP on macrophage polarization and its biological role in a mouse DSS-induced colitis model. The results showed that YAP upregulation in macrophages could induce M2 polarization and increase the levels of anti-inflammatory cytokines such as IL-10 and IL-13. In addition, when mice were infused with YAP-overexpressing and empty vector-transfected macrophages, compared with control mice, YAP-overexpressing mice presented slower weight loss, a longer colon length, less intestinal inflammation, and a better arrangement of crypts. Moreover, macrophages in the lamina propria of the mouse colonic mucosa presented mainly the M2 phenotype in YAP-overexpressing macrophage-infused DSS-treated mice. Mechanistically, knockdown of the expression of the transcription factor TEAD4 in YAP-overexpressing macrophages inhibited macrophage M2 polarization and decreased anti-inflammatory cytokine expression, accompanied by the downregulated expression of C/EBPβ. Furthermore, silencing C/EBPβ following YAP overexpression suppressed M2 polarization. Chromatin immunoprecipitation revealed that TEAD4 was enriched at the C/EBPβ promoter region in YAP-overexpressing macrophages. Thus, YAP in macrophages regulates C/EBPβ expression through the transcription factor TEAD4, which mediates macrophage M2 polarization and inhibits the expression of inflammatory cytokines, thereby exerting inhibitory effects on intestinal inflammation and promoting mucosal healing in a colitis model.

Background: Besides conventional norms that recognize synovial fluid (SF) as a joint lubricant, nutritional channel, and a diagnostic tool in knee osteoarthritis (kOA), based on the authors previous studies, this study aims to define functional role of SF in kOA. Methods: U937, a monocytic, human myeloid cell line, was induced with progressive grades of kOA SF, and the induction response was assessed on various pro-inflammatory parameters. This 'SF challenge test model' was further extended to determine the impact of SF on U937 differentiation using macrophage-specific markers and associated transcription factor genes. Mitochondrial membrane potential changes in SF-treated cells were evaluated with fluorescent JC-1 probe. Results: a significant increase in nitric oxide, matrix metalloproteinase (MMP) 1, 13, and vascular endothelial growth factor (VEGF)-1 was noted in the induced cells. A marked increase was seen in CD68, CD86, and the transcription factors -activator protein (AP)-1, interferon regulatory factor (IRF)-1, and signal transducer and activator of transcription (STAT)-6 in the SF-treated cells indicating active monocytes to macrophage differentiation. Reduced mitochondrial membrane potential was reflected by a reduced red-to-green ratio in JC-1 staining. Conclusions: these results underline the active role of OA SF in stimulating and maintaining inflammation in joint cells, fostering monocyte differentiation into pro-inflammatory macrophages. The decline in the membrane potential suggestive of additional inflammatory pathway in OA via the release of pro-apoptotic factors and damaged associated molecular patterns (DAMPs) within the cells. Overall, biochemical modulation of SF warrants a potential approach to intervene inflammatory cascade in OA and mitigate its progression.

Fusobacterium nucleatum is strongly linked to colorectal cancer (CRC) progression, but its mechanisms for influencing macrophage polarization and tumor development are not well understood. We established an in vitro model of F. nucleatum infection in RAW264.7 macrophages to investigate these processes. Macrophage polarization was evaluated using scanning electron microscopy (SEM), real-time quantitative PCR (RT-qPCR), and immunofluorescence staining. RNA sequencing (RNA-Seq) identified differentially expressed genes (DEGs) and enriched pathways, focusing on the role of the NF-κB signaling pathway in macrophage polarization. F. nucleatum infection induced M2 polarization in RAW264.7 macrophages, as confirmed by SEM analysis and RT-qPCR validation. A total of 2,029 DEGs were identified after F. nucleatum infection, with 763 upregulated and 1,266 downregulated. GO and KEGG enrichment analysis showed that cytokine-cytokine receptor interaction, TNF signaling, and NF-κB signaling pathways are upregulated in macrophages after F. nucleatum infection, indicating enhanced cytokine activity and immune response. Key genes (Nfkb1, Nfkb2, Malt, Lta, Ltb, Tnf) and proteins (P50, P100) in the NF-κB pathway are upregulated, indicating the crucial role of the NF-κB pathway in M2 macrophage polarization. This study offers crucial evidence regarding the role of the NF-κB signaling pathway in modulating F. nucleatum-induced macrophage M2 polarization, underscoring its significance in the progression of colorectal cancer.

The immunomodulatory properties of hyaluronan and its derivatives are key to their use in medicine and tissue engineering. In this work we evaluated the capability of soluble tyramine-modified hyaluronan (THA) synthesized from hyaluronan of two molecular weights (low Mw = 280 kDa and high Mw = 1640 kDa) for polarization of THP-1 and peripheral blood mononuclear cells (PBMCs)-derived macrophages (MΦs). We demonstrate the polarization effects of the supplemented THA by flow cytometry and bead-based multiplex immunoassay for the THP-1 derived MΦs and by semi-automated image analysis from confocal microscopy, immunofluorescent staining utilizing CD68 and CD206 surface markers, RT-qPCR gene expression analysis, as well as using the enzyme-linked immunosorbent assay (ELISA) for PBMCs-derived MΦs. Our data indicate that supplementation with LMW THA drives changes in THP-1 derived MΦs towards a pro-inflammatory M1-like phenotype, whereas supplementation with the HMW THA leads to a more mixed profile with some features of both M1 and M2 phenotypes, suggesting either a heterogeneous population or a transitional state. For cells directly sourced from human patients, PMBCs-derived MΦs, results exhibit a higher degree of variability, pointing out a differential regulation of factors including IL-10 and CD206 between the two cell sources. While human primary cells add to the clinical relevance, donor diversity introduces wider variability in the dataset, preventing drawing strong conclusions. Nevertheless, the MΦs profiles observed in THP-1 derived cells for treatments with LMW and HMW THA are generally consistent with what might be expected for the treatment with non-modified hyaluronans of respective molecular weights, confirming the known association holds true for the chemically tyramine-modified hyaluronan. We stipulate that these responses will provide basis for more accurate in vivo representation and translational immunomodulatory guidance for the use of THA-based biomaterials to a wider biomaterials and tissue engineering communities.

Polarized macrophages undergo metabolic reprogramming, as well as extensive epigenetic and post-translational modifications (PTMs) switch. Metabolic remodeling and dynamic changes of PTMs lead to timely macrophage response to infection or antigenic stimulation, as well as its transition from a pro-inflammatory to a reparative phenotype. The transformation of metabolites in the microenvironment also determines the PTMs of macrophages. Here we reviewed the current understanding of the altered metabolites of glucose, lipids and amino acids in macrophages shape signaling and metabolism pathway during macrophage polarization via PTMs, and how these metabolites in some macrophage-associated diseases affect disease progression by shaping macrophage PTMs.

The pathophysiology of intracerebral hemorrhage (ICH) is complex and can cause variable degrees of cell death. Recently, ferroptosis, an emerging cell death mechanism, has garnered significant attention in cerebral hemorrhage disorder. This study aimed to examine iron mortality after cerebral hemorrhage and current targets for potential therapeutic interventions. We specifically focused on iron metabolism abnormalities, lipid peroxidation, and related neuroinflammation and introduced molecular mechanisms, including transcription factors, to gain a better understanding of the underlying mechanisms of ferroptosis and investigate possible therapeutic options for ICH.

Ulcerative colitis (UC) is a chronic autoimmune disease and seriously affects the normal life of patients. Conventional therapeutic drugs are difficult to meet clinical needs. Traditional Chinese medicine (TCM) ingredients could effectively alleviate the symptoms of UC by anti-inflammatory, anti-oxidative, regulating the gut microbiota, and repairing the colonic epithelial barrier, but their low solubility and bioavailability severely limit their clinical application. Nano-drug delivery systems (NDDS) combined with TCM ingredients is a promising option for treating UC, and they could significantly enhance the stability, solubility, and bioavailability of TCM ingredients. The review describes the anti-UC mechanisms of TCM ingredients, systematically summarizes various kinds of NDDS for TCM ingredients according to different routes of administration, and highlights the advantages of NDDS for TCM ingredients in the treatmentof UC. In addition, we discuss the limitations of existing NDDS for TCM ingredients and the development direction in the future. This review will provide a basis for the future development of anti-UC NDDS for TCM ingredients.

Glioblastomas are the most prevalent primary brain tumors and are associated with a dramatically poor prognosis. Despite an intensive treatment approach, including maximal surgical tumor removal followed by radio- and chemotherapy, the median survival for glioblastoma patients has remained around 18 months for decades. Glioblastoma is distinguished by its highly complex mechanisms of immune evasion and pronounced heterogeneity. This variability is apparent both within the tumor itself, which can exhibit multiple phenotypes simultaneously, and in its surrounding microenvironment. Another key feature of glioblastoma is its "cold" microenvironment, characterized by robust immunosuppression. Recent advances in single-cell RNA sequencing have uncovered new promising insights, revealing previously unrecognized aspects of this tumor. In this review, we consolidate current knowledge on glioblastoma cells and its microenvironment, with an emphasis on their biological properties and unique patterns of molecular communication through signaling pathways. The evidence underscores the critical need for personalized poly-immunotherapy and other approaches to overcome the plasticity of glioblastoma stem cells. Analyzing the tumor microenvironment of individual patients using single-cell transcriptomics and implementing a customized immunotherapeutic strategy could potentially improve survival outcomes for those facing this formidable disease.

Complete surgical resection of advanced breast cancer is highly challenging and often leaves behind microscopic tumor foci, leading to inevitable relapse. Postoperative formation of the immunosuppressive tumor microenvironment (TME) reduces the efficacy of immunotherapies against residual tumors. Although cytotoxic chemotherapeutics exert the capacity to intensify cancer immunotherapy via immunogenic cell death (ICD) effects, systemically administered chemo agents often cannot access residual tumor sites, and fail to elicit antitumor immune responses. Herein, we present a novel syringeable immunotherapeutic hydrogel (SiGel@SN38/aOX40) loaded with the DNA-targeting chemotherapeutic 7-ethyl-10-hydroxycamptothecin (SN38) and the anti-OX40 agonist antibody (aOX40). The sustained in-site release of SN38 and aOX40 activate the stimulator of interferon genes (STING) pathway, intensify type I interferons expression, synergistically facilitate dendritic cell (DC) activation, and initiate persistent T cell mediated immune responses within the surgical resection bed that eliminate residual tumors with no tumor recurrence in 120 days. Collectively, our designed SiGel@SN38/aOX40 induces robust and long-lasting tumoricidal immunity following breast cancer resection and exhibit immense potential for clinical translation.

Osteoarthritis (OA) is a common chronic degenerative joint disease. Recent studies have emphasized the crucial role of macrophages, particularly tissue-resident macrophages (Tissue-Resident Macrophages, TRMs), in the pathogenesis and progression of OA. Under physiological conditions, TRMs maintain joint homeostasis, but under various stimuli, they can polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes. An imbalance in macrophage polarization, favoring the M1 phenotype, leads to sustained inflammation, cartilage degradation, and osteophyte formation, further exacerbating OA symptoms and structural damage. This article reviews the current understanding of macrophage polarization in OA, with a particular emphasis on the mechanisms by which TRMs influence the joint microenvironment. It explores the therapeutic potential of drug molecular platforms aimed at regulating macrophage polarization, shifting the balance from pro-inflammatory M1 to anti-inflammatory M2. The discussion includes various pharmacological agents such as corticosteroids, hyaluronic acid derivatives, monoclonal antibodies, and bioactive molecules like Squid Type II Collagen (SCII) in modulating macrophage function and slowing OA progression. Additionally, the article examines advancements in gene therapy methods targeting macrophages, utilizing nanotechnology-based delivery systems to enhance the specificity and efficiency of macrophage phenotype regulation. Targeting TRMs through sophisticated drug molecular platforms presents a promising strategy for developing novel diagnostic and therapeutic interventions for osteoarthritis.