JOURNAL/nrgr/04.03/01300535-202511000-00031/figure1/v/2024-12-20T164640Z/r/image-tiff The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury. Regulation of shifting microglia polarization from M1 (neurotoxic and proinflammatory type) to M2 (neuroprotective and anti-inflammatory type) after spinal cord injury appears to be crucial. Tryptanthrin possesses an anti-inflammatory biological function. However, its roles and the underlying molecular mechanisms in spinal cord injury remain unknown. In this study, we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro . Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway. Additionally, we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury, inhibited neuronal loss, and promoted tissue repair and functional recovery in a mouse model of spinal cord injury. Finally, using a conditional co-culture system, we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis. Taken together, these results suggest that by targeting the cGAS/STING/NF-κB axis, tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.

Periodontitis is a common chronic inflammatory disease primarily caused by pathogenic microorganisms in the oral cavity. Without appropriate treatments, it may lead to the gradual destruction of the supporting tissues of the teeth. While current treatments can alleviate symptoms, they still have limitations, particularly in eliminating pathogenic bacteria, promoting periodontal tissue regeneration, and avoiding antibiotic resistance. In recent years, functional nanomaterials have shown great potential in the treatment of periodontitis due to their unique physicochemical and biological properties. This review summarizes various functionalization strategies of nanomaterials and explores their potential applications in periodontitis treatment, including metal-based nanoparticles, carbon nanomaterials, polymeric nanoparticles, and exosomes. The mechanisms and advances in antibacterial effects, immune regulation, reactive oxygen species (ROS) scavenging, and bone tissue regeneration are discussed in detail. In addition, the challenges and future directions of applying nanomaterials in periodontitis therapy are also discussed.

Theabrownin is a key contributor to the flavor and health benefits of dark tea, but its structural characterization and anti-inflammatory properties remain underexplored. This study systematically investigated the physicochemical characteristics and anti-inflammatory mechanisms of Tibetan dark tea theabrownin (TTB). Our findings demonstrate that TTB is a hydroxyl- and carboxyl-rich polyphenolic aromatic polymer, composed of polyphenols, lipids, polysaccharides, and proteins. TTB modulated the NF-κB/Nrf2 signaling pathway, reducing inflammatory cytokines and oxidative stress, which in turn led to a decreased M1/M2 macrophage ratio and alleviated systemic inflammation. Fecal metabolomics analysis indicated that TTB exerts anti-inflammatory effects potentially by regulating key microbial metabolites, such as allantoic acid, and critical metabolic pathways like purine metabolism, as well as the metabolism of lysine, cysteine, phenylalanine, and pyruvate, etc. These findings provide insights into TTB's physicochemical properties and its mechanisms in alleviating systematic inflammation, providing a theoretical basis for the health-promoting effects of Tibetan dark tea.

Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms. Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration. However, recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration, particularly in the context of traumatic injuries. Consequently, autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration. Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths, thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation. These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration. A range of autophagy-inducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries. This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration, summarizing the potential drugs and interventions that can be harnessed to promote this process. We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.

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.

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.

This study introduces hyaluronic acid-based (HA) hydrogel microspheres loaded with zinc oxide nanoparticles (ZnO-NPs) for the treatment of infectious bone defects. The microspheres were fabricated using a 3D-printing process, with a formulation consisting of 6 wt% HAD (methacrylated HA), 3 wt% AOHA (AMP-conjugated oxidized HA), 1 % BOHA (phenylboric acid-conjugated HA), 0.5 % photoinitiator, and 0.05 % ZnO-NPs. In vitro, the hydrogel microspheres demonstrated significant antibacterial activity against Staphylococcus aureus, with colony counts and biofilm inhibition assays showing a marked reduction in bacterial growth after 12 and 24 h. The release of antimicrobial peptides (AMPs) was enhanced in acidic conditions and in the presence of hyaluronidase. The microspheres also promoted osteogenic differentiation of bone marrow stromal cells (BMSCs), as evidenced by increased expression of osteogenic markers (ALP, OCN, OPN, and COL-1). In vivo, the hydrogel microspheres were tested in a rat skull defect model, showing significant bone regeneration, improved angiogenesis, and an anti-inflammatory response. These results indicate that ABOHA@ZnO hydrogel microspheres provide a promising strategy for treating infectious bone defects by combining antimicrobial, osteogenic.

Inflammatory bowel disease (IBD) involves gastrointestinal inflammation, due to intestinal epithelial barrier destruction caused by excessive immune activation. Conventional cell culture systems do not provide a model system that can recapitulate the complex interactions between epithelial cells, immune cells, and intestinal bacteria. To address this, we developed a microfluidic device that mimics the inflammatory response associated with microbial invasion of the intestinal mucosa. The device consisted of two media channels, an upper and a lower channel, and a porous membrane between these channels on which C2BBe1 intestinal epithelial cells were seeded to form a tight junction layer. Each electrode was placed in contact with both channels to continuously monitor the tight junction state. Fresh medium flow allowed bacterial numbers to be controlled and bacterial toxins to be removed, allowing co-culture of mammalian cells and bacteria. In addition, RAW264 macrophage cells were attached to the bottom of the lower channel. By introducing E. coli into the lower channel, the RAW264 cells were activated and produced TNF-α, successfully recapitulating a culture model of inflammation in which the C2BBe1cell tight junction layer was destroyed. The main structure of the device was initially made of polydimethylsiloxane to facilitate its widespread use, but with a view to introducing anaerobic bacteria in the future, a similar phenomenon was successfully reproduced using polystyrene. When TPCA-1, an IκB kinase 2 inhibitor was added into this IBD culture model, the tight junction destruction was significantly suppressed. The results suggest that this IBD culture model also is useful as a screening system for anti-IBD drugs.

Aneurysmal subarachnoid hemorrhage (aSAH) is a complex condition associated with high disability and mortality rates, leading to poor clinical outcomes. Previous observational studies have suggested a link between ion channel genes and aSAH, but the causal relationship remains uncertain. This study utilized Mendelian randomization (MR) to explore the causal association between ion channel genes and aSAH, employing 5 MR methods: inverse variance weighted (IVW), MR-Egger, maximum likelihood, weighted median, and weighted mode. If results from these methods are inconclusive, IVW will be prioritized as the primary outcome. Additionally, MR-Egger, MR-PRESSO, and Cochrane Q tests were conducted to assess heterogeneity and pleiotropy. The stability of MR findings was evaluated using the leave-one-out approach; Bonferroni correction tested the strength of the causal relationship between exposure and outcome. The MR analysis revealed that CACNA2D3 was positively correlated with aSAH (OR 1.245; 95% confidence intervals [CI] 1.008-1.537; P = .042), while ANO6 showed a negative correlation (OR 0.728; 95% CI 0.533-0.993; P = .045). Our findings indicate that increased expression of CACNA2D3 promotes aSAH whereas elevated levels of ANO6 inhibit it. Transcriptome data from intracranial aneurysm samples confirmed significant differential expression of CACNA2D3 and ANO6 between ruptured and unruptured groups. CACNA2D3 being higher in ruptured cases while ANO6 was more expressed in unruptured ones. Furthermore, GeneMANIA analysis along with functional enrichment provided insights into risk factors for aSAH. Through MR analysis, we established a causal link between ion channel genes and aSAH, which helps to better understand the pathogenesis of aSAH and provide new therapeutic targets.

The effectiveness of hard orthokeratology (OK) lenses in controlling myopia has been confirmed in clinical practice. However, there exist defects including wear discomfort, limited regulation of mechanical properties and geometry, and effectiveness inconsistency with the expected efficacy. Herein, we analyze the relationship between the mechanical properties of OK lenses and the vertex displacement of the human cornea through the finite element model. It is noted that the expected corneal deformation of 15-20 μm can be achieved by soft OK lenses with an elasticity modulus above 9 MPa, which is far lower than the 2.7 GPa of commercial OK lenses. No obvious displacement difference occurred when the elasticity modulus of the OK lenses exceeded 200 MPa. Thus, we propose the hypothesis of soft OK lenses based on hydrogel materials for controlling myopia. The soft OK lenses are fabricated by a two-step 3D printing technology using a multicomponent bioink containing methyl methacrylate, hydroxyethyl methacrylate, polyethylene glycol diacrylate, and 3-(trimethoxysilyl)propyl methacrylate (KH-570). The printed OK lenses possess comfort wear, high light transmittance, smooth surface, regulated elasticity modulus (from 33 to 535 MPa) and geometry, and excellent biocompatibility. Additionally, the effectiveness of soft OK lenses is confirmed through a porcine corneal model with obvious corneal deformation comparable to that of the commercial ones. This study demonstrates the feasibility of soft OK lenses for controlling myopia and provides support for the design and fabrication of soft OK lenses for comfortable wear.

Macrophages are innate immune cells which are involved in triggering inflammation. Growing evidence shows that, macrophages respond to intracellular and extracellular cues which makes them adopt either anti-inflammatory or pro-inflammatory functions and phenotypes. Immunometabolism has been identified as one of the prominent factors which contributes massively towards the cessation and the development of inflammation as an immune response to infections and autoimmune diseases. However, when inflammation is poorly regulated, it leads to dire consequences. This illustrates that, understanding the role of immunometabolism in the regulation of inflammation, is paramount. In view of this, the review investigated the role of metabolic pathways such as: glycolysis, tricarboxylic acid cycle, pentose phosphate pathway, fatty acid oxidation, amino acid metabolism in macrophage reprogramming. The role of the intermediates and enzymes associated with these metabolic pathways in the regulation of, macrophage reprogramming and polarisation or activation was also reviewed. It was unveiled that, manipulating metabolic intermediates and enzymes could impact cellular immunometabolism. This eventually influences macrophage reprogramming and thus influences the generation of either a pro-inflammatory or anti-inflammatory response.

Several viruses cause acute and chronic arthritis. Millions of people suffered from Chikungunya(CHIK) during the recent epidemics/outbreaks in Asia, Africa and the Americas. Almost 20-40 % failed to recover completely and suffered from chronic pain and arthritis sequel. A wide spectrum of clinical phenotypic arthritis was described. Non-specific arthralgias(NSA) and soft tissue pains were predominant although inflammatory arthritis (mostly undifferentiated)(IA-U) was substantial. Specifically, rheumatoid arthritis(RA) and spondyloarthritis(SpA) like disorders were described. The frequency of biomarkers such as rheumatoid factor(RF) was low. Arthritis was mostly non-erosive in population studies. Abnormal immune mechanisms and persistent specific CHIK virus (CHIKV) IgM and IgG antibodies were shown. The etiopathogenetic evidence was divided between intense joint tissue inflammation due to prolonged virus persistence and abnormal autoimmune mechanisms. There was no specific therapy. The symptomatic management was often combined with an empirical use of disease modifying anti rheumatoid drugs and steroids. Substantial research is required to address knowledge gaps and unravel evidence-based medicine.

Rheumatoid arthritis (RA), defined as Bi Zheng syndrome in traditional Chinese medicine (TCM), is a chronic inflammatory and autoimmune disease that can cause substantial articular degradation and impairment. In RA, the polarization of macrophages to a proinflammatoy phenotype contributes to chronic inflammation and joint injury. Soufeng sanjie formula (SF), a traditional Chinese formula used to treat RA, consists of Scolopendra subspinipes mutilans L. Koch, Buthus martensii Karsch, Astragalus membranaceus (Fisch), and Glycine max (L.) Merr seed coats and plays a role in the regulation of macrophage polarization. Vitamin D (VD), a specific activator of the vitamin D receptor (VDR), promotes the differentiation of M2 macrophages and significantly enhances the therapeutic effects of TCM on arthritis. However, whether SF can be combined with VD to regulate macrophage polarization and alleviate RA remains unclear.

In this study, we examined the regulatory mechanisms and therapeutic effects of the combination of SF and VD on macrophages in RA.

We used network pharmacology to analyze the targets and pathways of SF in RA. Clinical data were analyzed to confirm the expression of key targets. The RA immune landscape for cell-gene correlations was built using bioinformatics. A collagen-induced arthritis (CIA) model was established to evaluate the combined therapeutic effects of SF and VD on joint injury and inflammation. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting (WB), and immunofluorescence were used to assess the expression of key molecules in macrophages. Macrophage polarization was analyzed using flow cytometry.

SF acts on RA through multiple pathways, including hub genes, such as VDR, ABL1, DNMT1, and CXCR4. Immune infiltration analysis of RA showed that a reduction in the number of M2 macrophages significantly affected RA. Clinical data analysis and prognostic assessments corroborated the pivotal roles played by hub genes, such as VDR, ABL1, DNMT1, and CXCR4. Crucially, this study demonstrated a strong association between the key hub gene VDR and M2 macrophages. In vivo and in vitro models of RA showed that VD significantly improved the efficacy of SF against arthritis in CIA mice and stimulated macrophage polarization toward the M2 phenotype via modulation of the NOTCH3/DLL4 pathway. Furthermore, siRNA-mediated interference with the expression of VDR confirmed that the downregulation of VDR significantly activated the NOTCH3/DLL4 signaling pathway and blocked the regulation of SF combined with VD on the polarization of macrophages toward the M2 phenotype.

Our results demonstrate that the combination of SF and VD markedly improves the therapeutic effect of SF on RA via M2 macrophage differentiation through the VDR-NOTCH3/DLL4 signaling pathway. The VD-enhancing effect of SF in improving RA symptoms offers a new strategy and theoretical foundation for the clinical treatment of the condition.

Macrophages are a promising target for therapeutics in various applications such as regenerative medicine and immunotherapy for cancer. Due to their plastic nature, macrophages can switch from a non-activated state to activated with the smallest environmental change. For macrophages to be effective in their respective applications, screening for phenotypic changes is necessary to elucidate the cell response to different delivery vehicles, vaccines, small molecules, and other stimuli.

We created a sensitive and dynamic high-throughput screening method for macrophages based on the activation of NF-κB. For this reporter, we placed an mRFP1 fluorescence gene under the control of an inflammatory promoter, which recruits NF-κB response elements to promote expression during the inflammatory response in macrophages. We characterized the inflammatory reporter based on key markers of an inflammatory response in macrophages including TNF-α cytokine release and immunostaining for inflammatory and non-inflammatory cell surface markers. We compared gene delivery and inflammation of several clinically relevant viral vehicles and commercially available non-viral vehicles. Statistical analysis between groups was performed with a one-way ANOVA with post-hoc Tukey's test.

The reporter macrophages demonstrated a dynamic range after LPS stimulation with an EC50 of 0.61 ng/mL that was highly predictive of TNF-α release. Flow cytometry revealed heterogeneity between groups but confirmed population level shifts in pro-inflammatory markers. Finally, we demonstrated utility of the reporter by showing divergent effects with various leading gene delivery vehicles.

This screening technique developed here provides a dynamic, high-throughput screening technique for determining inflammatory response by mouse macrophages to specific stimuli. The method presented here provides insight into the inflammatory response in mouse macrophages to different viral and non-viral gene delivery methods and provides a tool for high-throughput screening of novel vehicles.

The online version contains supplementary material available at 10.1186/s44330-025-00030-x.

Pathological fibrosis, the excessive deposition of extracellular matrix and tissue stiffening that causes progressive organ dysfunction, underlies diverse chronic diseases. The fibrotic microenvironment is driven by the dynamic microenvironmental interaction between various cell types; macrophages and fibroblasts play central roles in fibrotic disease initiation, maintenance, and progression. Macrophage functional plasticity to microenvironmental stimuli modulates fibroblast functionality by releasing pro-inflammatory cytokines, growth factors, and matrix remodeling enzymes that promote fibroblast proliferation, activation, and differentiation into myofibroblasts. Activated fibroblasts and myofibroblasts serve as the fibrotic effector cells, secreting extracellular matrix components and initiating microenvironmental contracture. Fibroblasts also modulate macrophage function through the release of their own pro-inflammatory cytokines and growth factors, creating bidirectional crosstalk that reinforces the chronic fibrotic cycle. The intricate interplay between macrophages and fibroblasts, including their secretomes and signaling interactions, leads to tissue damage and pathological loss of tissue function. In this review, we examine macrophage-fibroblast reciprocal dynamic interactions in pathological fibrotic conditions. We discuss the specific lineages and functionality of macrophages and fibroblasts implicated in fibrotic progression, with focus on their signal transduction pathways and secretory signalling that enables their pro-fibrotic behaviour. We then finish with a set of recommendations for future experimentation with the goal of developing a set of potential targets for anti-fibrotic therapeutic candidates. Understanding the cellular interactions between macrophages and fibroblasts provides valuable insights into potential therapeutic strategies to mitigate fibrotic disease progression.

Insight into the immunopathology of polymyalgia rheumatica (PMR) is scarce and mainly derived from peripheral blood studies. The limited data available point towards macrophages as potential key players in PMR. This study aimed to identify the factors driving proinflammatory macrophage development and their functions in the immunopathology of PMR.

Monocyte phenotypes were investigated by flow cytometry in peripheral blood (PMR, n = 22; healthy controls, n = 20) and paired subacromial-subdeltoid (SASD) bursal fluid (PMR, n = 9). Macrophages in SASD bursa were characterised by immunohistochemistry and immunofluorescence (PMR, n = 12; controls undergoing shoulder replacement surgery, n = 10). The functions of cytokines expressed in PMR-affected tissue were examined using macrophage differentiation cultures (PMR, n = 7; healthy controls, n = 7).

Monocytes (CD14highCD16- and CD14highCD16+) were increased in blood of PMR patients and activated in bursal fluid. Macrophages dominated immune infiltrates in PMR-affected tissue, expressing various proinflammatory cytokines. While interleukin (IL)-6 and interferon-gamma (IFN-γ) expression was abundant in both PMR and control tissue, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) were significantly increased in PMR tissue. Macrophages in PMR-affected tissue showed an elevated CD206/folate receptor β ratio, reflecting a GM-CSF skewed signature. A combination of GM-CSF/M-CSF/IFN-γ significantly boosted IL-6 production in vitro, while limited IL-6 production was observed without GM-CSF.

The monocyte compartment is expanded and activated in PMR. Macrophages in PMR-affected tissue produce abundant proinflammatory cytokines such as IL-6. A network of locally expressed cytokines, including GM-CSF, M-CSF, and IFN-γ, may drive the proinflammatory functions of these macrophages. Overall, macrophages may constitute key therapeutic targets for PMR.

Extracellular vesicles (EVs) are small particles released by various cells, including cancer cells. They play a significant role in the development of different cancers, including brain metastasis. These EVs transport biomolecular materials such as RNA, DNA, and proteins from tumour cells to other cells, facilitating the spread of primary tumours to the brain tissue. EVs interact with the endothelial cells of the blood-brain barrier (BBB), compromising its integrity and allowing metastatic cells to pass through easily. Additionally, EVs interact with various cells in the brain's microenvironment, creating a conducive environment for incoming metastatic cells. They also influence the immune system within this premetastatic environment, promoting the growth of metastatic cells. This review paper focuses on the research regarding the role of EVs in the development of brain metastasis, including their impact on disrupting the BBB, preparing the premetastatic environment, and modulating the immune system. Furthermore, the paper discusses the potential of EVs as diagnostic and prognostic biomarkers for brain metastasis.

Inflammation is a precursor to atherosclerotic plaque destabilisation, leading to ischaemic events like stroke. Since macrophage phenotypes can be influenced by their microenvironment, we aimed to stabilise plaques and reduce the risk of recurrent ischaemic events using clinically relevant anti-inflammatory agents.

Thirteen carotid plaques from stroke/Transient Ischaemic Attack (TIA) patients undergoing carotid endarterectomy were analysed using immunofluorescence stain to identify macrophage markers (CD68, CD86, MRC1). An in vitro model of human blood-derived macrophages was used to evaluate the effects of statins and glucocorticoids on macrophage-specific markers using RT-qPCR, Western Blot, and immunofluorescence staining. The physiological effects of dexamethasone on macrophages and human carotid plaques were further studied ex vivo.

The macrophage population (CD68+) in the carotid plaques was dominated by "double-positive" (CD86+MRC1+) macrophages (67.8 %), followed by "M1-like" (CD86+MRC1-) (16.5 %), "M2-like" (CD86-MRC1+) (8.7 %) and "double-negative" (CD86-MRC1-) (7.0 %) macrophages. M1-like macrophages were more prevalent in unstable plaque sections than stable ones (p = 0.0022). Exposure to dexamethasone increased macrophage MRC1 gene expression in vitro and ex vivo. It also reduced the expression of the Oxidised Low-Density Lipoprotein Receptor 1 (OLR1) gene and protein, leading to reduced oxLDL uptake in foam cell assays.

Clinically relevant concentrations of glucocorticoids may shift human macrophages to a less inflammatory state, thus reducing their ability for oxidised LDL uptake. In contrast, this anti-inflammatory mechanism was not observed in response to statins. These findings suggest that glucocorticoids could help prevent ischemic events in patients with advanced atherosclerosis.

Acute lung injury (ALI) has high clinical mortality currently and no specific drugs available for its treatment. Although Liang-Ge-San (LGS), a traditional Chinese medicine formula, is known to promote inflammation resolution and shorten hospitalization duration of ALI, the mechanism is still unclear. Our results demonstrated that LGS regulated the dynamic balance of macrophage polarization as reflected by up-regulating the expression of anti-inflammatory factors (CD206, Arg-1 and IL-10) in advance to counteract the high expression of pro-inflammatory factors (CD86, iNOS, IL-6 and TNF-α) in vitro. MiR-21 concentration was elevated in LPS-challenged RAW264.7 cells and ALI mice. Moreover, the overexpression of miR-21 mimicked the anti-inflammatory effects of LGS, whereas a miR-21 inhibitor abolished the protective effects of LGS in vitro. Most importantly, LGS protected ALI mice from LPS which could be counteracted by the treatment of miR-21 antagomir. Furthermore, LGS could inhibit the transcriptional activity and protein expression of PTEN by up-regulating miR-21. In summary, LGS functions by regulating the miR-21/PTEN axis to induce a shift in macrophages from a pro-inflammatory phenotype to an anti-inflammatory phenotype, thereby alleviating LPS-induced ALI. This study supports the clinical evidence of LGS in the treatment of ALI.

To investigate the potential of emodin in promoting nerve regeneration following PNI by targeting macrophage polarization, NLRP3 inflammasome activation, autophagy, and the EGFR/PI3K/Akt/mTOR pathway. A cohort of 78 male Sprague-Dawley rats was used to develop models of sciatic nerve damage, with an additional 18 rats in the sham surgery group. The rats were randomly assigned to eight groups: Sham, Control, PNI + Emodin (20 mg/kg), PNI + Emodin (80 mg/kg), PNI + MCC950 (10 mg/kg), PNI + Rapamycin (2 mg/kg), PNI + Emodin (80 mg/kg) + 3-MA (15 mg/kg), and PNI + Emodin (80 mg/kg) + NSC 228155 (5 mg/kg). Emodin was administered intragastrical daily, while the inhibitors or agonist were administered via intraperitoneal injection, as per the respective dosages and schedules. The treatment period included assessments of nerve regeneration and functional recovery, such as histological staining, immunofluorescence for cellular markers, TEM for ultrastructural changes, SFI for functional recovery, and western blot analysis for autophagy and inflammatory proteins. IF and TEM images showed that emodin enhanced axonal and myelin regeneration. Histological analysis revealed emodin reduced muscular atrophy and collagen deposition. Emodin decreased pro-inflammatory macrophage markers (CD68) while increasing M2 markers (CD206), inhibited the NLRP3 inflammasome, and reduced IL-1β and caspase-1. It activated autophagy in Schwann cells, with increased LC3-II levels. Network pharmacology and molecular docking identified EGFR in the PI3K/AKT/mTOR pathway as a key target, with emodin inhibiting EGFR activation. This study reveals that emodin promotes early nerve recovery by enhancing functional outcomes, axonal remyelination, and reducing muscle atrophy. It boosts autophagy in Schwann cells, inhibits NLRP3 inflammasome activation, and promotes M2 macrophage polarization. These effects are closely related to the EGFR/PI3K/AKT/mTOR pathway.

Infection with H. pylori induces chronic gastric inflammation, progressing to peptic ulcer and stomach adenocarcinoma. Macrophages function as innate immune cells and play a vital role in host immune defense against bacterial infection. However, the distinctive mechanism by which H. pylori evades phagocytosis allows it to colonize the stomach and further aggravate gastric preneoplastic pathology. H. pylori exacerbates gastric inflammation by promoting oxidative stress, resisting macrophage phagocytosis, and inducing M1 macrophage polarization. M2 macrophages facilitate the proliferation, invasion, and migration of gastric cancer cells. Various molecular mechanisms governing macrophage function in the pathogenesis of H. pylori infection have been identified. In this review, we summarize recent findings of macrophage interactions with H. pylori infection, with an emphasis on the regulatory mechanisms that determine the clinical outcome of bacterial infection.

Mediating protein citrullination, peptidyl arginine deiminase 2 (PAD2) has recently been reported to influence macrophage phenotypes. However, the mechanisms of PAD2 on macrophage function in Pseudomonas aeruginosa (PA)-induced acute lung injury syndrome (ALI) remains unclear. Utilizing single-cell RNA sequencing and mass spectrometry-based proteomics, a new citrullination site at arginine 171 (R171) is discovered within nuclear factor- κB (NF-κB) p65 catalyzed by PAD2, which modulates PAD2-NF-κB p65-importin α3 pathway and its downstream M1/M2 macrophage polarization. Building on these findings, a cell-specific targeted therapeutic strategy using gold nanoparticles (AuNPs) conjugated with a novel PAD2 inhibitor, AFM41a, and an intercellular adhesion molecule-1 (ICAM-1) antibody is developed. This approach enables the selective delivery of the inhibitor to M1-polarized macrophages in the PA-infected alveolar niche. In vivo, this nanomedicine reduces excessive inflammation and promotes M1-to-M2 polarization to inhibit ALI. This study highlights the role of PAD2-mediated citrullination in macrophage polarization and introduces a promising nanoparticle-based therapy for PA-induced ALI.

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.

Inflammation and progressive fibrosis represent predictive risk factors for heart failure (HF) development following myocardial infarction (MI). Peptidylargininine deiminase 4 (PAD4) catalyzes the citrullination of arginine residues in polypeptides and has recently been identified as a contributor to HF pathogenesis. This study aimed to evaluate the role of PAD4 in monocytes / macrophages (Mo/Mφ) and cardiac fibroblasts (CFs) for cardiac repair following MI and HF progression. Cardiac Padi4 expression significantly increased in mice subjected to MI by permanent coronary artery ligation as well as in humans who died from MI. Transcriptome analysis revealed marked downregulation of inflammation-related genes in infarcted hearts and cardiac Mo/Mφ from global PAD4 knockout (PAD4-/-) mice on day 7 post-MI accompanied by increased frequency of reparative CD206+ macrophages. Mechanistically, pharmacological and genetic PAD4 inhibition abrogated nuclear NF-κB translocation and inflammatory gene expression in bone marrow-derived macrophages (BMDM). Simultaneously, reduced inflammation and diminished cardiac levels of transforming growth factor-β (TGF-β) along with impaired IL-6 / TGF-β signaling in PAD4-/- CFs were associated with decreased expression of fibrotic genes, reduced collagen deposition, improved cardiac function, and enhanced 28-day survival in PAD4-/- mice. Strikingly, whereas pharmacological PAD inhibition in the acute phase after MI exacerbated cardiac damage, treatment starting on day 7 ameliorated cardiac remodeling and improved long-term survival in mice. Collectively, we here identified PAD4 as a critical regulator of inflammatory genes in Mo/Mφ and of profibrotic pathways in CFs. Thus, therapeutic approaches directed against PAD4 are promising interventions to alleviate adverse cardiac remodeling and subsequent HF development.

Urinary tract infection (UTI), a common clinical infectious disease, is marked by high incidence and frequent recurrence. Recurrent UTIs can cause severe complications, negatively affecting health. The emergence and spread of drug-resistant bacteria present significant challenges to UTI treatment. This article systematically reviews the key immune mechanisms in the body's defense against UTI pathogens. It discusses various immune response components, such as the urinary tract mucosal epithelium, neutrophils, macrophages, dendritic cells, mast cells, innate lymphocytes, T cells, and B cells, with the aim of providing insights for future UTI research.

Calycosin, a naturally occurring isoflavonoid found predominantly in Astragalus membranaceus, exhibits significant therapeutic potential in various neurological conditions. Its multifaceted bioactive properties-antioxidant, anti-inflammatory, and anti-apoptotic-position it as a promising candidate for neuroprotection and neuroregeneration. This review explores calycosin's mechanisms of action, including its modulation of key signaling pathways such as HMGB1/TLR4/NF-κB (high mobility group box 1/toll-like receptor 4/nuclear factor kappa B), phosphatidylinositol-3-kinase (PI3 K)/Akt, ERK1/2 (extracellular signal-regulated kinase 1/2), and Hsp90/Akt/p38. In cerebral ischemia/reperfusion injury, calycosin reduces oxidative stress markers like ROS (reactive oxygen species) and MDA (malondialdehyde), enhances antioxidant enzymes (SOD (superoxide dismutase) and GPX (glutathione peroxidase)), and downregulates pro-inflammatory cytokines (TNF-α, IL-1β) through the HMGB1/TLR4/NF-κB pathway. It also inhibits autophagy via the STAT3/FOXO3a pathway and apoptosis by modulating Bax and Bcl-2 expression. In neuro-oncology, calycosin inhibits glioblastoma cell migration and invasion by modulating the TGF-β-mediated mesenchymal properties and suppressing the c-Met and CXCL10 signaling pathways. Additionally, it enhances the efficacy of temozolomide in glioma treatment through apoptotic pathways involving caspase-3 and caspase-9. Calycosin shows promise in Alzheimer's disease by reducing β-amyloid production and tau hyperphosphorylation via the GSK-3β pathway and improving mitochondrial function through the peroxisome proliferator-activated receptor gamma coactivator 1-Alpha (PGC-1α)/mitochondrial transcription factor A (TFAM) signaling pathway. In Parkinson's disease, calycosin mitigates oxidative stress, prevents dopaminergic neuronal death, and reduces neuroinflammation by inhibiting the TLR/NF-κB and MAPK pathways. It has also shown therapeutic potential in meningitis and even neuroprotective effects against hyperbilirubinemia-induced nerve injury. Despite these promising findings, further research, including detailed mechanistic studies and clinical trials, is needed to fully understand calycosin's therapeutic mechanisms and validate its potential in human subjects. Developing advanced delivery systems and exploring synergistic therapeutic strategies could further enhance its clinical application and effectiveness.

Sepsis-induced cardiomyopathy (SIC) presents a critical complication in cancer patients, contributing notably to heart failure and elevated mortality rates. While its clinical relevance is well-documented, the intricate molecular mechanisms that link sepsis, tumor-driven inflammation, and cardiac dysfunction remain inadequately explored. This study aims to elucidate the interaction between post-tumor inflammation, intratumor heterogeneity, and the dysfunction of VSMC in SIC, as well as to evaluate the therapeutic potential of exercise training and specific pharmacological interventions.

Transcriptomic data from NCBI and GEO databases were analyzed to identify differentially expressed genes (DEGs) associated with SIC. Weighted gene co-expression network analysis (WGCNA), gene ontology (GO), and KEGG pathway enrichment analyses were utilized to elucidate the biological significance of these genes. Molecular docking and dynamics simulations were used to investigate drug-target interactions, and immune infiltration and gene mutation analyses were carried out by means of platforms like TIMER 2.0 and DepMap to comprehend the influence of DVL1 on immune responsiveness.

Through the utilization of the datasets, we discovered the core gene DVL1 that exhibited remarkable up-regulated expression both in SIC and in diverse kinds of cancers, which were associated with poor prognosis and inflammatory responses. Molecular docking revealed that Digoxin could bind to DVL1 and reduce oxidative stress in SIC. The DVL1 gene module related to SIC was identified by means of WGCNA, and the immune infiltration analysis demonstrated the distinctive immune cell patterns associated with DVL1 expression and the impact of DVL1 on immunotherapeutic resistance.

DVL1 is a core regulator of SIC and other cancers and, therefore, can serve as a therapeutic target. The present study suggests that targeted pharmacological therapies to enhance response to exercise regimens may be a novel therapeutic tool to reduce the inflammatory response during sepsis, particularly in cancer patients. The identified drugs, Digoxin, require further in vivo and clinical studies to confirm their effects on SIC and their potential efforts to improve outcomes in immunotherapy-resistant cancer patients.

Here we present a microfluidic model that allows for co-culture of human osteoblasts, chondrocytes, fibroblasts, and macrophages of both quiescent (M0) and pro-inflammatory (M1) phenotypes, maintaining initial viability of each cell type at 24 h of co-culture. We established healthy (M0-based) and diseased (M1-based) joint models within this system. An established disease model based on supplementation of IFN-γ and lipopolysaccharide in cell culture media was used to induce an M1 phenotype in macrophages to recapitulate inflammatory conditions found in Osteoarthritis. Cell viability was assessed using NucBlue™ Live and NucGreen™ Dead fluorescent stains, with mean viability of 83.9% ± 14% and 83.3% ± 12% for healthy and diseased models, respectively, compared with 93.3% ± 4% for cell in standard monoculture conditions. Cytotoxicity was assessed via a lactate dehydrogenase (LDH) assay and showed no measurable increase in lactate dehydrogenase release into the culture medium under co-culture conditions, indicating that neither model promotes a loss of cell membrane integrity due to cytotoxic effects. Cellular metabolic activity was assessed using a PrestoBlue™ assay and indicated increased cellular metabolic activity in co-culture, with levels 5.9 ± 3.2 times mean monolayer cell metabolic activity levels in the healthy joint model and 5.3 ± 3.4 times mean monolayer levels in the diseased model. Overall, these findings indicate that the multi-tissue nature of in vivo human joint conditions can be recapitulated by our microfluidic co-culture system at 24 h and thus this model serves as a promising tool for studying the pathophysiology of rheumatic diseases and testing potential therapeutics.

Macrophages perform an essential role in the body's defense mechanisms and tissue homeostasis. These cells exhibit plasticity and are categorized into two phenotypes, including classically activated/M1 pro-inflammatory and alternatively activated/M2 anti-inflammatory phenotypes. Functional deviation in macrophage polarization occurs in different pathological conditions that need correction. In addition to antidiabetic impacts, metformin also possesses multiple biological activities, including immunomodulatory, anti-inflammatory, anti-tumorigenic, anti-aging, cardioprotective, hepatoprotective, and tissue-regenerative properties. Metformin can influence the polarization of macrophages toward M1 and M2 phenotypes. The ability of metformin to support M2 polarization and suppress M1 polarization could enhance its anti-inflammatory properties and potentiate its protective effects in conditions such as chronic inflammatory diseases, atherosclerosis, and obesity. However, in metformin-treated tumors, the proportion of M2 macrophages is decreased, while the frequency ratio of M1 macrophages is increased, indicating that metformin can modulate macrophage polarization from a pro-tumoral M2 state to an anti-tumoral M1 phenotype in malignancies. Metformin affects macrophage polarization through AMPK-dependent and independent pathways involving factors, such as NF-κB, mTOR, ATF, AKT/AS160, SIRT1, STAT3, HO-1, PGC-1α/PPAR-γ, and NLRP3 inflammasome. By modulating cellular metabolism and apoptosis, metformin can also influence macrophage polarization. This review provides comprehensive evidence regarding metformin's effects on macrophage polarization and the underlying mechanisms. The polarization-inducing capabilities of metformin may provide significant therapeutic applications in various inflammatory diseases and malignant tumors.

Gemcitabine combined with cisplatin is the first-line chemotherapy for advanced cholangiocarcinoma, but drug resistance remains a challenge, leading to unsatisfactory therapeutic effect. Here, we elucidate the possibility of chemotherapy regimens sensitized by inhibiting succinylation in patients with cholangiocarcinoma from the perspective of post-translational modification. Our omics analysis reveals that succinylation of PDHA1 lysine 83, a key enzyme in the tricarboxylic acid cycle, alters PDH enzyme activity, modulates metabolic flux, and leads to alpha-ketoglutaric acid accumulation in the tumor microenvironment. This process activates the OXGR1 receptor on macrophages, triggering MAPK signaling and inhibiting MHC-II antigen presentation, which promotes immune escape and tumor progression. Moreover, we show that inhibiting PDHA1 succinylation with CPI-613 enhances the efficacy of gemcitabine and cisplatin. Targeting PDHA1 succinylation may be a promising strategy to improve treatment outcomes in cholangiocarcinoma and warrants further clinical exploration.

Although extensive antibiotic regimens have been implemented to address pathogen-infected pneumonia, existing strategies are constrained in their efficacy against intracellular bacteria, a prominent contributor to antibiotic resistance. In addition, the concurrent occurrence of a cytokine storm during antibiotic therapy presents a formidable obstacle in the management of pneumonia caused by pathogens. In the present study, an infection-targeting system that leverages M2-macrophage-derived vesicles [exosomes (Exos)] as vehicles to convey antibiotics (antibiotics@Exos) was developed for effective pneumonia management. The proposed system can enable antibiotics to be specifically delivered to infected macrophages in pneumonia through homotypic recognition and was found to exhibit an exceptional intracellular bactericidal effect. Moreover, M2-type vesicles exhibit a high degree of efficiency in reprogramming inflammatory macrophages toward an anti-inflammatory phenotype. As a result, the administration of antibiotics@Exos was found to substantical decrease the level of the infiltrated inflammatory cells and alleviate the inflammatory factor storm in the lungs of acute lung injury mice. This intervention resulted in the alleviation of reactive-oxygen-species-induced damage, reduction of pulmonary edema, and successful pneumonia treatment. This bioactive vesicle delivery system effectively compensates for the limitations of traditional antibiotic therapy regimens with pluralism effects, paving a new strategy for serious infectious diseases, especially acute pneumonia treatment.

Ginsenosides, the principal active ingredients in ginseng, have anti-bacterial, anti-inflammatory, antioxidant, anticancer, osteogenic, cardioprotective, and neuroprotective properties. Oral diseases afflict about half of the world's population. Ginsenosides' multifunctional properties have led to substantial investigation into their potential to prevent and treat oral disorders. However, their low absorption and poor targeting limit their effectiveness.

This review summarizes the latest research progress on ginsenoside-based drug delivery systems and the potential of ginsenosides in preventing and treating oral diseases to provide a theoretical basis for clinical applications.

Using "ginsenoside", "drug delivery", "nanoparticles", "liposomes", "hydrogel", "oral disease", "toxicology", "pharmacology", "clinical translation" and combinations of these keywords in PubMed, Web of Science, and Science Direct. The search was conducted until December 2024.

The limitations of natural ginsenosides can be overcome by utilizing drug delivery systems to improve pharmacological activity, bioavailability and targeting. The multifunctional pharmacological activities of ginsenosides offer promising avenues for treating oral diseases. In addition, the susceptibility of the oral cavity to infection by pathogenic bacteria and the diluting effect of saliva pose significant challenges to treatment. The emergence of drug delivery marks a breakthrough in addressing these issues.

Ginsenoside-based drug delivery methods improve bioactivity, targeting, and reduce costs. This review emphasizes current advancements in ginsenosides within novel drug delivery systems, specifically on its potential in preventing and treating oral disorders. However, multiple well-designed clinical trials are needed to further evaluate the efficacy and safety of these drugs.

Peripheral nerve regeneration after trauma poses a substantial clinical challenge that has already been investigated for many years. Infiltration of immune cells is a critical step in the response to nerve damage that creates a supportive microenvironment for regeneration. In this work, we focus on a special type of immune cell, macrophage, in addressing the problem of neuronal regeneration. We discuss the complex endogenous mechanisms of peripheral nerve injury and regrowth vis-à-vis macrophages, including their recruitment, polarization, and interplay with Schwann cells post-trauma. Furthermore, we elucidate the underlying mechanisms by which exogenous stimuli govern the above events. Finally, we summarize the necessary roles of macrophages in peripheral nerve lesions and reconstruction. There are many challenges in controlling macrophage functions to achieve complete neuronal regeneration, even though considerable progress has been made in understanding the connection between these cells and peripheral nerve damage.

Diabetes, which is a systemic disease, increases susceptibility to destructive periodontal diseases, which are characterized by infectious susceptibility, but the potential mechanisms remain unknown. The aim of this study was to investigate the mechanism of high glucose environment promoting the occurrence and development of local periodontal inflammation.

In this study, the effects of neutrophil extracellular traps (NETs) on macrophage polarization and the mechanism were designed to verify whether this course plays a role in periodontal tissue impairment associated with diabetes. Here, we examined the impact of NETs on macrophages in vitro. NETs were isolated from cultures of neutrophils exposed to hyperglycemia. Mouse models of diabetic periodontitis (DP) and macrophage polarization were developed, and the degrees of NET formation in the periodontal tissue of DP mice were assessed. Furthermore, western blotting was performed to analyze the related mechanisms.

The results revealed that hyperglycemia induced the formation of NETs, and abundant NET formation led to proinflammatory cytokine secretion by macrophages and low expression of JAK-2 and STAT-3 in vitro and in vivo. NETs regulated macrophage polarization through the JAK/STAT pathway.

These results suggest that NETs target proinflammatory cytokine secretion via the JAK/STAT pathway and may play important roles in DP progression and macrophage polarization, which indicates that therapeutically referring to this regulatory pathway might be a promising method for treating diabetes-associated inflammatory diseases.

Stem cell transplantation is a promising treatment for repairing damaged tissues, but challenges like immune rejection and ethical concerns remain. Mesenchymal stem cells (MSCs) offer high differentiation potential and immune regulatory activity, showing promise in treating diseases such as gynecological, neurological, and kidney disorders. With scientific progress, MSC applications are overcoming traditional treatment limitations. In MSCs-macrophage coculture, MSCs transform macrophages into anti-inflammatory M2 macrophages, reducing inflammation, whereas macrophages enhance MSCs osteogenic differentiation. This coculture is vital for immune modulation and tissue repair, with models varying by contact type and dimensional arrangements. Factors such as coculture techniques and cell ratios influence outcomes. Benefits include improved heart function, wound healing, reduced lung inflammation, and accelerated bone repair. Challenges include optimizing coculture conditions. This study reviews the methodologies, factors, and mechanisms of MSC-macrophage coculture, providing a foundation for tissue engineering applications. SIGNIFICANCE STATEMENT: This review underlines the significant role of mesenchymal stem cell-macrophage coculture, providing a foundation for tissue engineering application.

Crohn's disease (CD) is characterized by immune cell dysregulation, with macrophages playing an indisputable role. Macrophages can exhibit opposing polarization under different conditions, resulting in pro- or anti-inflammatory effects. The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, is implicated in intestinal inflammation by regulating both innate and adaptive immune responses. However, the regulatory mechanism between AhR and macrophages in colitis has not been thoroughly investigated.

Macrophage polarization in the colonic tissue of active CD patients was assessed. Following colitis induction in mice by 2,4,6-trinitro-benzenesulfonic acid (TNBS), an intraperitoneal injection of the natural AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) was administered. The severity of colitis was estimated, and macrophage polarization was detected. In an in vitro setting, bone marrow-derived macrophages (BMDMs) were polarized to the M2 phenotype in the presence or absence of FICZ. Interferon regulatory factor 4 (IRF4) siRNA was applied to knockdown IRF4 expression. M2-specific markers were quantified using quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry.

Compared with healthy controls, active CD patients exhibited a lower presence of M2 macrophages in colonic tissue. Experimentally, FICZ was found to protect mice against TNBS-induced colitis, as evidenced by reduced diarrhea, bloody stool, and weight loss. This effect was associated with an increase in M2 macrophages and the release of IL-10 in the intestine. In BMDMs, FICZ promoted the expressions of M2-specific markers, including Ym1, Fizz1, IL-10, and CD206. Furthermore, FICZ upregulated IRF4 expression. After IRF4 silencing with siRNA, the enhancement of macrophage M2 polarization by FICZ was significantly impaired.

Activation of AhR appears to have a beneficial effect on intestinal inflammation by promoting macrophage M2 polarization. This effect is partially mediated by the upregulation of IRF4 expression and may lead to new insight into the pathogenesis of CD.

Macrophage polarization is a dynamic process driven by a complex interplay of cytokine signaling, metabolism, and epigenetic modifications mediated by pathogens. Upon encountering specific environmental cues, monocytes differentiate into macrophages, adopting either a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype, depending on the cytokines present. M1 macrophages are induced by interferon-gamma (IFN-γ) and are characterized by their reliance on glycolysis and their role in host defense. In contrast, M2 macrophages, stimulated by interleukin-4 (IL-4) and interleukin-13 (IL-13), favor oxidative phosphorylation and participate in tissue repair and anti-inflammatory responses. Metabolism is tightly linked to epigenetic regulation, because key metabolic intermediates such as acetyl-coenzyme A (CoA), α-ketoglutarate (α-KG), S-adenosylmethionine (SAM), and nicotinamide adenine dinucleotide (NAD+) serve as cofactors for chromatin-modifying enzymes, which in turn, directly influences histone acetylation, methylation, RNA/DNA methylation, and protein arginine methylation. These epigenetic modifications control gene expression by regulating chromatin accessibility, thereby modulating macrophage function and polarization. Histone acetylation generally promotes a more open chromatin structure conducive to gene activation, while histone methylation can either activate or repress gene expression depending on the specific residue and its methylation state. Crosstalk between histone modifications, such as acetylation and methylation, further fine-tunes macrophage phenotypes by regulating transcriptional networks in response to metabolic cues. While arginine methylation primarily functions in epigenetics by regulating gene expression through protein modifications, the degradation of methylated proteins releases arginine derivatives like asymmetric dimethylarginine (ADMA), which contribute directly to arginine metabolism-a key factor in macrophage polarization. This review explores the intricate relationships between metabolism and epigenetic regulation during macrophage polarization. A better understanding of this crosstalk will likely generate novel therapeutic insights for manipulating macrophage phenotypes during infections like tuberculosis and inflammatory diseases such as diabetes.

Hypertrophic Scar (HS) is a common fibrotic disease of the skin, usually caused by injury to the deep dermis due to trauma, burns, or surgical injury. The main feature of HS is the thickening and hardening of the skin, often accompanied by itching and pain, which seriously affects the patient's quality of life. Macrophages are involved in all stages of HS genesis through phenotypic changes. M1-type macrophages primarily function in the early inflammatory phase by secreting pro-inflammatory factors, while M2-type macrophages actively contribute to tissue repair and fibrosis. Despite advances in understanding HS pathogenesis, the precise mechanisms linking macrophage phenotypic changes to fibrosis remain incompletely elucidated. This review addresses these gaps by discussing the pathological mechanisms of HS formation, the phenotypic changes of macrophages at different stages of HS formation, and the pathways through which macrophages influence HS progression. Furthermore, emerging technologies for HS treatment and novel therapeutic strategies targeting macrophages are highlighted, offering potential avenues for improved prevention and treatment of HS.