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.

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.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder among fertile women, which is influenced by genetics and environment. A recent study revealed that PCOS patients were in a chronic inflammatory state, and they had abnormally activated macrophages. This paper introduces the relationship between PCOS and macrophages. The forkhead box protein O1 (FOXO-1), migration inhibitory factor, sympathetic conservation disorder, and vitamin D are believed to influence macrophages in PCOS. There is evidence that PCOS-associated abnormalities are associated with macrophages, including insulin resistance, obesity, hyperandrogenism (HA), hyperhomocysteinemia (HHcy), cardiometabolic disorder and gut microbiota dysbiosis. This review summarizes the research status of macrophages in PCOS. Macrophages might be a potential PCOS treatment candidate.

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.

Sepsis, a severe systemic inflammatory condition triggered by infection, is associated with high morbidity and mortality worldwide. While medical diagnosis and treatment have advanced in recent years, a specific therapy remains unavailable. Recently, significant progress has been made in studying the epigenetic RNA modification N6-methyladenosine (m6A) and its core methyltransferase METTL3. The role of m6A in sepsis has also been increasingly elucidated. This review aims to explore the pathological mechanisms of sepsis and its relationship with m6A, focusing on the role of the key m6A writer, METTL3, in sepsis.

Mucopolysaccharidosis (MPS) encompasses a heterogeneous group of lysosomal storage diseases resulting from mutations in genes encoding lysosomal enzymes responsible for the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs). Current therapeutic strategies for MPS include hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT), and symptomatic therapy. This study investigated dynamic changes in MPS type II (MPS-II) through genomic and single-cell sequencing in a patient undergoing ERT. Analysis of peripheral blood mononuclear cells (PBMCs) from one MPS-II patient of 10 year old at different disease stages through scRNA-seq identified various immune cell types, including natural killer (NK) cells, NKT cells, CD4 + and CD8 + T cells, CD14 + and CD16 + monocytes, and B cells. Monocytes and macrophages were significantly reduced during the severe stage of MPS-II but increased during the recovery stage following ERT. Notably, monocyte subtype mono3 was exclusively expressed in the severe stage, while mono1_2, a subtype of mono1, was absent during the severe stage and exhibited distinct biological functions. These findings suggest that monocytes and macrophages play critical roles in the pathogenesis of MPS-II and in the response to ERT. Pseudotime, Gene Ontology, and cell-communication analyses revealed unique functions for the different cellular subtypes. Notably, key molecules mediating cellular interactions during ERT in MPS-II included CXCR3, PF4, APP, and C5AR1 in macrophages, RPS19 in T cells, HLA-DPB1 in B cells, ADRB2 in NK cells, and IL1B, C5AR1, RPS19, and TNFSF13B in monocytes. Overall, integrative analysis delineated the expression dynamics of various cell types and identified mutations in MPS-II, providing a comprehensive atlas of transcriptional programs, cellular characterizations, and genomic variation profiles in MPS-II. This dataset, along with advanced integrative analysis, represents a valuable resource for the discovery of drug targets and the improvement of therapeutic strategies for MPS-II.

Potassium voltage-gated channel subfamily A regulatory beta subunit 2 (KCNAB2) is a potassium voltage-gated channel subfamily A member that plays a role in non-small cell lung cancer (NSCLC). However, its functional impact and mechanism in NSCLC are not fully understood. Here, we analyzed its effects on NSCLC cell behaviors and the underlying mechanism.mRNA expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR),(qRT-PCR), while protein expression was quantified by western blotting blot analysis or immunohistochemistry assay. NSCLC cell proliferation, migration, invasion, macrophage polarization, and apoptosis were evaluated through cell-based assays including cell counting kit-8 (CCK-8)(CCK-8) assay, flow cytometry, Tunel assay, wound-healing assay, and transwell invasion assay. The role of FTO alpha-ketoglutarate dependent dioxygenase (FTO)-mediated(FTO)-mediated m6A methylation in the regulation of KCNAB2 expression and their impacts on NSCLC cell behavior and M2 macrophage polarization were assessed through m6A RNA immunoprecipitation assay and rescue experiments. Xenograft mouse model assay was used to determine the effect of KCNAB2 on tumor formation in vivo.in vivo.KCNAB2 expression was downregulated and FTO expression was upregulated in NSCLC tissues and cells when compared with controls. Moreover, the expression of KCNAB2 was found to be lower in stage III NSCLC patients compared to those at stages I and II, and it was also lower in patients with positive lymph node metastasis compared to those with negative lymph node metastasis. Overexpression of KCNAB2 inhibited NSCLC cell proliferation, migration, invasion, and M2 macrophage polarization, while inducing cell apoptosis. These effects were mediated, at least partially, by inactivating the phosphoinositide 3-kinase (PI3K)/AKT(PI3K)/AKT pathway. Moreover, ectopic expression of KCNAB2 delayed tumor formation in vivo. FTOin vivo. FTO was found to mediate m6A methylation of KCNAB2, and knockdown of FTO resulted in the upregulation of KCNAB2 expression, leading to inhibition of NSCLC cell behavior and M2 macrophage polarization.KCNAB2 overexpression inhibited NSCLC cell behavior and M2 macrophage polarization by inactivating the PI3KPI3K/AKT/AKT pathway. Furthermore, FTOFTO-mediated-mediated m6A methylation was involved in the regulation of KCNAB2 expression in NSCLC. These results enhance our understanding of the role of KCNAB2 in NSCLC and suggest its potential as a therapeutic target.

Nel-like molecule-1 (Nell-1), as a novel osteo-inductive molecule with great potential for clinical applications, has various functions including promoting chondrogenesis, suppressing osteoclastic activity, promoting osteogenesis, suppressing inflammation and promoting vascularization. Its anti-inflammatory potential has been widely studied. However, its anti-inflammatory potential in macrophage and possible underlying molecular mechanisms are poorly understood. Therefore, the present study aims to evaluate the anti-inflammatory potential and the regulation to macrophage polarization of Nell-1 in human myeloid cell line (THP-1) derived macrophages. M1-related markers and M2-related markers were studied in THP-1 derived macrophages. The suppressive potential of Nell-1 on lipopolysaccharide (LPS)-induced translocation of nuclear factor-kappa B (NF-κB) in THP-1 macrophage was studied. Results showed that Nell-1 significantly reduced M1 macrophage-related surface marker cluster of differentiation 86 (CD86) and inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) and reversed the LPS-induced M1 polarization of macrophages by upregulating the M2-specific markers of vascular endothelial growth factor (VEGF), arginase-1(Arg-1), and cluster of differentiation 206 (CD206) in vitro. In addition, the possible mechanism of the anti-inflammatory effects of Nell-1 is via regulating NF-κB pathway. Hence, Nell-1 is a potential suppressor of inflammation and is involved in the regulation of macrophage polarization. Nell-1 may be a potential candidate for treating inflammatory diseases and promoting tissue regeneration.

The interaction between immune cells brings a consequence either on their role and functioning or the functioning of the other immune cells, modulating the whole mechanistic pathway. The interaction between natural killer (NK) cells and macrophages is one such interaction which is relatively less explored amongst diseased conditions. Their significance comes from their innate nature and secretion of large proportions of cytokines and chemokines which results in influencing adaptive immune responses. Their interplay can lead to several functional outcomes such as NK cell activation/inhibition, increased cytotoxicity and IFNγ release by NK cells, inhibition of macrophage function, etc. This paper delves into the interaction amongst NK cells and macrophages via different receptor-ligands and cytokines, particularly emphasising microbial infections and tumours. The review has the potential to uncover new insights and approaches that could lead to the development of innovative therapeutic tools and targets.

Primary and post-primary TB are distinct entities. Primary TB occurs when the patient is infected with Mycobacterium tuberculosis (MTB) for the first time without prior immunity, and post-primary TB occurs when the patient has developed immunity against the primary infection. Post-primary TB occurs only in humans. It accounts for 80% of all clinical cases and nearly 100% of transmissions of infection. Early lesions of post-primary TB are reversible, and studying it using modern immunological tools holds the key to developing preventive or treatment strategies. Human lung tissue from untreated TB patients was acquired from pathology archives stored at the Gades Institute of Pathology, Haukeland University Hospital, Bergen, Norway, from 1931 to 1947. Manual immunohistochemistry was performed for macrophage (CD68, CD64 and CD163), T cells (CD3 and CD8), matrix metalloproteinases (MMP-9), and markers for programmed death-pathway PD/PDL-1. Digital quantification was performed using Qupath software. In early lesions of post-primary TB, macrophages showed mixed-phenotype M1 and M2, expressed PDL-1, and were compartmentalized in the alveolar space. T-cells expressed PD-1 and were compartmentalized in the interstitial wall surrounding early lesions. MTB antigens and MMP-9 were also found in early lesions. As the lesion progressed towards necrosis, macrophages showed predominant M1 morphology, and expressions of PDL-1, PD-1, CD8+ cells, and MTB antigens increased. In the early lesions of post-primary TB, the compartmentalization of macrophages in the alveoli and T cells in the interstitium was shown. The PDL-PD1 pathway probably facilitated the mycobacterial growth by evading host immunity.

Skeletal muscle wasting is commonly observed in aging, immobility, and chronic diseases. In pathological conditions, the impairment of skeletal muscle and immune system often occurs simultaneously. Recent studies have highlighted the initiative role of skeletal muscle in interactions with immune cells. However, the impact of skeletal muscle wasting on macrophage inflammatory responses remains poorly understood.

To investigate the effect of atrophic myotubes on the inflammatory response of macrophages, we established two in vitro models to induce myotube atrophy: one induced by D-galactose and the other by starvation. Conditioned medium (CM) from normal and atrophic myotubes were collected and administered to bone marrow-derived macrophages (BMDMs) from mice. Subsequently, lipopolysaccharide (LPS) stimulation was applied, and the expression of inflammatory cytokines was measured via RT-qPCR.

Both D-galactose and starvation treatments reduced myotube diameter and upregulated muscle atrophy-related gene expression. CM from both atrophic myotubes models augmented the gene expression of pro-inflammatory factors in BMDMs following LPS stimulation, including Il6, Il1b, and Nfkb1. Notably, CM from starvation-induced atrophic myotubes also enhanced Il12b, Tnf, and Nos2 expression in BMDMs after stimulation, a response not observed in D-galactose-induced atrophic myotubes.

These findings suggest that CM from atrophic myotubes enhanced the expression of LPS-induced pro-inflammatory mediators in macrophages.

Sepsis-induced acute lung injury (SALI) is characterized by a dysregulated inflammatory and immune response. As a key component of the innate immune system, macrophages play a vital role in SALI, in which a macrophage phenotype imbalance caused by an increase in M1 macrophages or a decrease in M2 macrophages is common. Despite significant advances in SALI research, effective drug therapies are still lacking. Therefore, the development of new treatments for SALI is urgently needed. An increasing number of studies suggest that natural products (NPs) can alleviate SALI by modulating macrophage polarization through various targets and pathways. This review examines the regulatory mechanisms of macrophage polarization and their involvement in the progression of SALI. It highlights how NPs mitigate macrophage imbalances to alleviate SALI, focusing on key signaling pathways such as PI3K/AKT, TLR4/NF-κB, JAK/STAT, IRF, HIF, NRF2, HMGB1, TREM2, PKM2, and exosome-mediated signaling. NPs influencing macrophage polarization are classified into five groups: terpenoids, polyphenols, alkaloids, flavonoids, and others. This work provides valuable insights into the therapeutic potential of NPs in targeting macrophage polarization to treat SALI.

Macrophages are key players in maintaining the balance of tissues and dealing with inflammation, carrying out vital functions specific to different tissues while safeguarding the body against infections. The intricate interplay between oxidative stress and macrophage polarization and how this contributes to pneumonia is not fully understood. Herein, a predominant accumulation of baicalein in lung macrophages of pathogen-infected mice was observed by an alkynyl-modified probe. Baicalein effectively reduces oxidative stress in vivo and in vitro by modulating the KEAP1-NRF2/ARE signaling pathway. Further investigation indicated that baicalein has inhibitory effects on M1 macrophage polarization and phagocytic capacity, reducing inflammatory cytokine expression. As a protein-protein interaction (PPI) inhibitor, baicalein disrupts the KEAP1-NRF2 interaction by competitively binding to the DGR/Kelch domain of KEAP1. This process helps NRF2 move to the nucleus, which activates the antioxidant transcriptional program, suppresses the production of reactive oxygen species (ROS), and mitigates oxidative stress damage. These findings suggest a different approach to developing treatments for oxidative stress that focuses on inhibiting the interaction between KEAP1-NRF2.

Major depressive disorder (MDD), as a multimodal neuropsychiatric and neurodegenerative illness with high prevalence and disability rates, has become a burden to world health and the economy that affects millions of individuals worldwide. Neuroinflammation, an atypical immune response occurring in the brain, is currently gaining more attention due to its association with MDD. Microglia, as immune sentinels, have a vital function in regulating neuroinflammatory reactions in the immune system of the central nervous system. From the perspective of steady-state branching states, they can transition phenotypes between two extremes, namely, M1 and M2 phenotypes are pro-inflammatory and anti-inflammatory, respectively. It has an intermediate transition state characterized by different transcriptional features and the release of inflammatory mediators. The timing regulation of inflammatory cytokine release is crucial for damage control and guiding microglia back to a steady state. The dysregulation can lead to exorbitant tissue injury and neuronal mortality, and targeting the cellular signaling pathway that serves as the regulatory basis for microglia is considered an essential pathway for treating MDD. However, the specific intervention targets and mechanisms of microglial activation pathways in neuroinflammation are still unclear. Therefore, the present review summarized and discussed various signaling pathways and effective intervention targets that trigger the activation of microglia from its branching state and emphasizes the mechanism of microglia-mediated neuroinflammation associated with MDD.

Epigenetic modifications have been identified as critical molecular determinants influencing macrophage plasticity and heterogeneity. Among these, histone lactylation is a recently discovered epigenetic modification. Research examining the effects of histone lactylation on macrophage activation and polarization has grown substantially in recent years. Evidence increasingly suggests that lactate-mediated changes in histone lactylation levels within macrophages can modulate gene transcription, thereby contributing to the pathogenesis of various diseases. This review provides a comprehensive analysis of the role of histone lactylation in macrophage activation, exploring its discovery, effects, and association with macrophage diversity and phenotypic variability. Moreover, it highlights the impact of alterations in macrophage histone lactylation in diverse pathological contexts, such as inflammation, tumorigenesis, neurological disorders, and other complex conditions, and demonstrates the therapeutic potential of drugs targeting these epigenetic modifications. This mechanistic understanding provides insights into the underlying disease mechanisms and opens new avenues for therapeutic intervention.

Neferine (Nef) has a renal protective effect. This research intended to explore the impact of Nef on hyperuricemic nephropathy (HN).

Adenine and potassium oxonate were administered to SD rats to induce the HN model. Bone marrow macrophages (BMDM) and NRK-52E were used to construct a transwell co-culture system. The polarization of BMDM and apoptosis levels were detected using immunofluorescence and flow cytometry. Renal pathological changes were detected using hematoxylin-eosin (HE) and Masson staining. Biochemical methods were adopted to detect serum in rats. CCK-8 and EDU staining were used to assess cell activity and proliferation. RT-qPCR and western blot were adopted to detect NLRC5, NLRP3, pyroptosis, proliferation, and apoptosis-related factor levels.

After Nef treatment, renal injury and fibrosis in HN rats were inhibited, and UA concentration, urinary protein, BUN, and CRE levels were decreased. After Nef intervention, M1 markers, pyroptosis-related factors, and NLRC5 levels in BMDM stimulated with uric acid (UA) treatment were decreased. Meanwhile, the proliferation level of NRK-52E cells co-cultured with UA-treated BMDM was increased, but the apoptosis level was decreased. After NLRC5 overexpression, Nef-induced regulation was reversed, accompanied by increased NLRP3 levels. After NLRP3 was knocked down, the levels of M1-type markers and pyroptosis-related factors were reduced in BMDM.

Nef improved HN by inhibiting macrophages polarized to M1-type and pyroptosis by targeting the NLRC5/NLRP3 pathway. This research provides a scientific theoretical basis for the treatment of HN.

Chronic liver disease has a substantial global prevalence and mortality rate. Macrophages, pivotal cells in innate immunity, exhibit remarkable heterogeneity and plasticity and play a considerable role in maintaining organ homeostasis, modulating inflammatory responses, and influencing disease progression in the liver. Exosomes, which can serve as conduits for intercellular communication, biomarkers, and therapeutic targets for a spectrum of diseases, have recently garnered increasing attention recently. Given that the liver is the organ with the highest macrophage content, a thorough understanding of the influence of macrophage-derived exosomes (MDEs) on noncancer liver disease pathogenesis and their potential therapeutic applications is paramount. Interactions among MDEs, hepatocytes, hepatic stellate cells (HSCs), and other nonparenchymal cells constitute a complex network regulates liver immune homeostasis. In this review, we summarize the latest progress in the current understanding of MDE heterogeneity and cellular crosstalk in noncancer liver diseases, as well as their potential clinical applications. Additionally, challenges and future directions are underscored.

Alveolar bone healing is influenced by various local and systemic factors, including the local inflammatory response. This study aimed to evaluate the role of inflammatory responsiveness in alveolar bone healing using 8-week-old male and female mice (N = 5/time/group) strains selected for maximum (AIRmax) or minimum (AIRmin) acute inflammatory response carrying distinct homozygous RR/SS Slc11a1 genotypes, namely AIRminRR, AIRminSS, AIRmaxRR, and AIRmaxSS mice. After upper right incisor extraction, bone healing was analyzed at 0, 3, 7, and 14 days using micro-computed tomography, histomorphometry, birefringence, immunohistochemistry, and PCRArray analysis. AIRmaxSS and AIRminRR presented the highest and lowest inflammatory readouts, respectively, associated with lowest repair levels in both strains, while intermediate inflammatory phenotypes observed in AIRminSS and AIRmaxRR were associated with higher repair levels in such strains. The better healing outcomes are associated with intermediate inflammatory cell counts, a balanced expression of pro- and anti-inflammatory cytokines and chemokines, increased expression of growth and osteogenic factors and MSCs markers. Our results demonstrate that extreme high and low inflammatory responses are not ideal for a proper bone repair outcome, while an intermediate and transitory inflammation is associated with a proper alveolar bone healing outcome.

Sepsis is a systemic inflammatory response caused by an infection, which can easily lead to acute lung injury. Quiescin Q6 sulfhydryl oxidase 1 (QSOX1) is a sulfhydryl oxidase involved in oxidative stress and the inflammatory response. However, there are few reports on the role of QSOX1 in sepsis-induced acute lung injury (SALI). In this study, mice model of SALI was constructed by intraperitoneal injection with lipopolysaccharide (LPS). The increased inflammatory response and lactate dehydrogenase activity in bronchoalveolar lavage fluid (BALF) indicated successful modeling. Increased QSOX1 expression was both observed in lung tissues and lung macrophages of sepsis mice accompanied by increased polarization of M1-type macrophages. To explore the role of QSOX1 in the SALI, lentivirus containing QSOX1-specific overexpression or knockdown vectors were used to change QSOX1 expression in LPS-treated RAW264.7 cells. QSOX1 suppressed LPS-induced M1 polarization and further inhibited inflammatory response in RAW264.7 cells. Interestingly, the phosphorylation of epidermal growth factor receptor (EGFR), the promoter of M1 polarization in macrophages, was found to be downregulated upon QSOX1 overexpression in RAW264.7 cells. Mechanically, the binding of QSOX1 to EGFR protein promoted EGFR ubiquitination and degradation, thereby down-regulating EGFR phosphorylation. Moreover, inhibiting EGFR expression or its phosphorylation restored the impact of QSOX1 silencing on M1 polarization and inflammation in the LPS-treated RAW264.7 cells. In summary, QSOX1 may exert anti-inflammatory effects in SALI by inhibiting EGFR phosphorylation-mediated M1 macrophage polarization. This presented a potential target for the treatment and prevention of SALI.

Immunotherapy has emerged as a highly effective therapeutic strategy for cancer treatment. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) pathway activation facilitates tumor-associated macrophage (TAM) polarization toward M1 phenotype, and Mn2+ are effective agents for this pathway activation. However, the high in vivo degradation rate and toxicity of Mn2+ hamper clinical application of immunotherapy. Here, this work has newly synthesized and screened manganese porphyrins for Mn2+ transport, referred to as photo-STING agonists (PSAs), and further encapsulate them into core-shell nanoparticles named Rm@PP-GA with dual specificity for tumor tissue and TAMs. Not only do PSAs achieve higher Mn2+ delivery efficiency compared to Mn2+, but they also generate reactive oxygen species under light exposure, promoting mitochondrial DNA release for cGAS-STING pathway activation. In Rm@PP-GA, globin and red blood cell membranes (Rm) are used for erythrocyte efferocytosis-mimicking delivery. Rm can effectively prolong the in vivo circulation period while globin enables PSAs to be taken up by TAMs via CD163 receptors. After Rm rupture mediated by perfluorohexane in nanoparticles under ultrasonication, drugs are specifically released for TAM repolarization. Further, dendritic cells mature, as well as T lymphocyte infiltrate, both of which favor tumor eradication. Therefore, cancer immunotherapy is optimized by novel PSAs delivered by erythrocyte efferocytosis-mimicking delivery pattern.

Ferroptosis is a newly identified form of programmed cell death that is connected to iron-dependent lipid peroxidization. It involves a variety of physiological processes involving iron metabolism, lipid metabolism, oxidative stress, and biosynthesis of nicotinamide adenine dinucleotide phosphate, glutathione, and coenzyme Q10. So far, it has been discovered to contribute to the pathological process of many diseases, such as myocardial infarction, acute kidney injury, atherosclerosis, and so on. Macrophages are innate immune system cells that regulate metabolism, phagocytize pathogens and dead cells, mediate inflammatory reactions, promote tissue repair, etc. Emerging evidence shows strong associations between macrophages and ferroptosis, which can provide us with a deeper comprehension of the pathological process of diseases and new targets for the treatments. In this review, we summarized the crosstalk between macrophages and ferroptosis and anatomized the application of this association in disease treatments, both non-neoplastic and neoplastic diseases. In addition, we have also addressed problems that remain to be investigated, in the hope of inspiring novel therapeutic strategies for diseases.

Exercise can regulate the immune function, activate the activity of immune cells, and promote the health of the organism, but the mechanism is not clear. Skeletal muscle is a secretory organ that secretes bioactive substances known as myokines. Exercise promotes skeletal muscle contraction and the expression of myokines including irisin, IL-6, BDNF, etc. Here, we review nine myokines that are regulated by exercise. These myokines have been shown to be associated with immune responses and to regulate the proliferation, differentiation, and maturation of immune cells and enhance their function, thereby serving to improve the health of the organism. The aim of this article is to review the effects of myokines on intrinsic and adaptive immunity and the important role that exercise plays in them. It provides a theoretical basis for exercise to promote health and provides a potential mechanism for the correlation between muscle factor expression and immunity, as well as the involvement of exercise in body immunity. It also provides the possibility to find a suitable exercise training program for immune system diseases.

Red blood cells (RBCs) naturally trap some bacterial pathogens in the circulation and kill them by oxidative stress. Following neutralization, the bacteria are presented to antigen-presenting cells in the spleen by the RBCs. This ability of RBCs has been harnessed to develop a system where they play a crucial role in enhancing the immune response, offering a novel approach to enhance the body's immunity. In this work, a conjugate, G-OVA, was formed by connecting β-glucan and OVA through a disulfide bond. Poly (lactic-co-glycolic acid) (PLGA) was then employed to encapsulate G-OVA, yielding G-OVA-PLGA. Finally, the nanoparticles were adsorbed onto RBCs to develop G-OVA-PLGA@RBC. The results demonstrated that the delivery of nanoparticles by RBCs enhanced the antibody response to antigens both in vitro and in vivo. The objective of this study was to investigate the increased immune activity of G-OVA-PLGA nanoparticles facilitated by RBCs transportation and to elucidate some of its underlying mechanisms. These findings are anticipated to contribute valuable insights for the development of efficient and safe immune enhancers.

In immunology, the role of macrophages extends far beyond their traditional classification as mere phagocytes; they emerge as pivotal architects of the immune response, with their function being significantly influenced by multidimensional environmental stimuli. This review investigates the nuanced mechanisms by which diverse external signals ranging from chemical cues to physical stress orchestrate macrophage polarization, a process that is crucial for the modulation of immune responses. By transitioning between pro-inflammatory (M1) and anti-inflammatory (M2) states, macrophages exhibit remarkable plasticity, enabling them to adapt to and influence their surroundings effectively. The exploration of macrophage polarization provides a compelling narrative on how these cells can be manipulated to foster an immune environment conducive to tissue repair and regeneration. Highlighting cutting-edge research, this review presents innovative strategies that leverage the dynamic interplay between macrophages and their environment, proposing novel therapeutic avenues that harness the potential of macrophages in regenerative medicine. Moreover, this review critically evaluates the current challenges and future prospects of translating macrophage-centered strategies from the laboratory to clinical applications.

Intestinal flora metabolites played a crucial role in immunomodulation by influencing host immune responses through various pathways. Macrophages, as a type of innate immune cell, were essential in chemotaxis, phagocytosis, inflammatory responses, and microbial elimination. Different macrophage phenotypes had distinct biological functions, regulated by diverse factors and mechanisms. Advances in intestinal flora sequencing and metabolomics have enhanced understanding of how intestinal flora metabolites affect macrophage phenotypes and functions. These metabolites had varying effects on macrophage polarization and different mechanisms of influence. This study summarized the impact of gut microbiota metabolites on macrophage phenotype and function, along with the underlying mechanisms associated with different metabolites produced by intestinal flora.

Macrophage type 1 (M1) cells are associated with both acute kidney injury (AKI) during kidney transplantation and acute rejection (AR) after kidney transplantation. Our study explored M1-related biomarkers involved in both AKI and AR and their potential biological functions.

Based on the Gene Expression Omnibus (GEO) database, the immune cell infiltration levels and differentially expressed genes were examined in AKI and AR in the kidney transplantation; M1-related genes shared in AKI and AR were identified using weighted gene co-expression analysis (WGCNA) system. Subsequently, protein-protein interaction (PPI) networks and machine learning methods to identify Hub genes and construct diagnostic models. Both AKI model and AR rat models were built to validate the expressions of Hub genes and test the injury phenotype, oxidative stress markers, and inflammatory factors. Finally, the transcription factor (TF)-Hub gene and micro-RNA (miRNA)-Hub gene regulatory networks were constructed based on identified Hub genes.

Out of 2167 differential expression genes (DEGs) in AKI and 2100 DEGs in AR, four M1-related Hub genes were obtained by PPI networks and machine learning methods, namely GBP2, TYROBP, CCR5, and TLR8. The calibration curves in the nomogram diagnostic model for these four Hub genes suggested the same predictive probability as an ideal model for AKI and AR after kidney transplantation (AUC values of the area under the ROC curve were all >0.7). The same observations were confirmed in ischemia reperfusion injury (IRI) and AR rat models by identifying common four Hub genes (GBP2, TYROBP, TLR8, and CCR5). Western blots showed that these four Hub genes were significantly different in rat models of IRI and AR (all p<0.05). Compared with the control group, IRI and AR groups showed aggravated histopathological damage and increased secretion of oxidative stress markers and inflammatory factors in rat kidneys (all p<0.05). Finally, TF-Hub and miRNA-Hub gene regulatory networks were constructed to provide a theoretical basis for the regulation of Hub genes.

We identified four macrophage M1-related Hub genes shared among AKI and AR after kidney transplantation. These genes may be considered for diagnosis of AKI and AR after kidney transplantation.

Macrophages play an essential role in immunotherapy and tissue regeneration owing to their remarkable plasticity and diverse functions. Recent bioengineering developments have focused on using external physical stimuli such as electric and magnetic fields, temperature, and compressive stress, among others, on micro/nanostructures to induce macrophage polarization, thereby increasing their therapeutic potential. However, it is difficult to find a concise review of the interaction between physical stimuli, advanced micro/nanostructures, and macrophage polarization. This review examines the present research on physical stimuli-induced macrophage polarization on micro/nanoplatforms, emphasizing the synergistic role of fabricated structure and stimulation for advanced immunotherapy and tissue regeneration. A concise overview of the research advancements investigating the impact of physical stimuli, including electric fields, magnetic fields, compressive forces, fluid shear stress, photothermal stimuli, and multiple stimulations on the polarization of macrophages within complex engineered structures, is provided. The prospective implications of these strategies in regenerative medicine and immunotherapeutic approaches are highlighted. This review will aid in creating stimuli-responsive platforms for immunomodulation and tissue regeneration.

Acute myocardial infarction is one of the most important causes of death in the world, causing a huge health and economic burden to the world. It is still a ticklish problem how to effectively prevent reperfusion injury while recovering the blood flow of ischemic myocardium. During the process of myocardial ischemia/reperfusion injury (MI/RI), the modulation of immune cells plays an important role. Monocyte/macrophage, neutrophils and endothelial cells initiate the inflammatory response and induce the release of various inflammatory cytokines, resulting in increased vascular permeability, tissue edema and damage. Meanwhile, T cells were recruited to impaired myocardium and release pro-inflammatory and anti-inflammatory cytokines. T cells and macrophages play important roles in keeping cardiac homeostasis and orchestrate tissue repair. T cells differentiation and macrophages polarization precisely regulates the tissue microenvironment in MI/RI, and shows cross action, but the mechanism is unclear. To identify potential intervention targets and propose ideas for treatment and prevention of MI/RI, this review explores the crosstalk between T lymphocytes and macrophages in MI/RI.

As a natural immune cell and antigen presenting cell, macrophages have been studied and engineered to treat human diseases. Macrophages are well-suited for use as drug carriers because of their biological characteristics, such as excellent biocompatibility, long circulation, intrinsic inflammatory homing and phagocytosis. Meanwhile, macrophages' uniquely high plasticity and easy re-education polarization facilitates their use as part of efficacious therapeutics for the treatment of inflammatory diseases or tumors. Although recent studies have demonstrated promising advances in macrophage-based drug delivery, several challenges currently hinder further improvement of therapeutic effect and clinical application. This article focuses on the main challenges of utilizing macrophage-based drug delivery, from the selection of macrophage sources, drug loading, and maintenance of macrophage phenotypes, to drug migration and release at target sites. In addition, corresponding strategies and insights related to these challenges are described. Finally, we also provide perspective on shortcomings on the road to clinical translation and production.

The role of cathepsin K (CTSK) expression in the pathogenesis and progression of gastric cancer (GC) remains unclear. Hence, the primary objective of this study is to elucidate the precise expression and biological role of CTSK in GC by employing a combination of bioinformatics analysis and in vitro experiments. Our findings indicated a significant upregulation of CTSK in GC. The bioinformatics analysis revealed that GC patients with a high level of CTSK expression exhibited enrichment of hallmark gene sets associated with angiogenesis, epithelial-mesenchymal transition (EMT), inflammatory response, KRAS signaling up, TNFα signaling via KFκB, IL2-STAT5 signaling, and IL6-JAK-STAT3 signaling. Additionally, these patients demonstrated elevated levels of M2-macrophage infiltration, which was also correlated with a poorer prognosis. The results of in vitro experiments provided confirmation that the over-expression of CTSK leads to an increase in the proliferative and invasive abilities of GC cells. However, further evaluation was necessary to determine the impact of CTSK on the migration capability of these cells. Our findings suggested that CTSK has the potential to facilitate the initiation and progression of GC by augmenting the invasive capacity of GC cells, engaging in tumor-associated EMT, and fostering the establishment of an immunosuppressive tumor microenvironment (TME).

Diabetic heart disease (DHD) is a serious complication in patients with diabetes. Despite numerous studies on the pathogenic mechanisms and therapeutic targets of DHD, effective means of prevention and treatment are still lacking. The pathogenic mechanisms of DHD include cardiac inflammation, insulin resistance, myocardial fibrosis, and oxidative stress. Macrophages, the primary cells of the human innate immune system, contribute significantly to these pathological processes, playing an important role in human disease and health. Therefore, drugs targeting macrophages hold great promise for the treatment of DHD. In this review, we examine how macrophages contribute to the development of DHD and which drugs could potentially be used to target macrophages in the treatment of DHD.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Macrophages are key effector cells that play a central role in RA pathogenesis through their ability to polarize into distinct functional phenotypes. An imbalance favoring pro-inflammatory M1 macrophages over anti-inflammatory M2 macrophages disrupts immune homeostasis and exacerbates joint inflammation. Multiple signaling pathways, including Notch, JAK/STAT, NF-κb, and MAPK, regulate macrophage polarization towards the M1 phenotype in RA. Metabolic reprogramming also contributes to this process, with M1 macrophages prioritizing glycolysis while M2 macrophages utilize oxidative phosphorylation. Redressing this imbalance by modulating macrophage polarization and metabolic state represents a promising therapeutic strategy. Furthermore, complex bidirectional interactions exist between synovial macrophages and fibroblast-like synoviocytes (FLS), forming a self-perpetuating inflammatory loop. Macrophage-derived factors promote aggressive phenotypes in FLS, while FLS-secreted mediators contribute to aberrant macrophage activation. Elucidating the signaling networks governing macrophage polarization, metabolic adaptations, and crosstalk with FLS is crucial to developing targeted therapies that can restore immune homeostasis and mitigate joint pathology in RA.

Acne vulgaris is one of the most common skin diseases. The current understanding of acne primarily revolves around inflammatory responses, sebum metabolism disorders, aberrant hormone and receptor expression, colonization by Cutibacterium acnes, and abnormal keratinization of follicular sebaceous glands. Although the precise mechanism of action remains incompletely understood, it is plausible that macrophages exert an influence on these pathological features. Macrophages, as a constituent of the human innate immune system, typically manifest distinct phenotypes across various diseases. It has been observed that the polarization of macrophages toward the M1 phenotype plays a pivotal role in the pathogenesis of acne. In recent years, extensive research on acne has revealed an increasing number of natural remedies exhibiting therapeutic efficacy through the modulation of macrophage polarization. This review investigates the role of cutaneous macrophages, elucidates their potential significance in the pathogenesis of acne, a prevalent chronic inflammatory skin disorder, and explores the therapeutic mechanisms of natural plant products targeting macrophages. Despite these insights, the precise role of macrophages in the pathogenesis of acne remains poorly elucidated. Subsequent investigations in this domain will further illuminate the pathogenesis of acne and potentially offer guidance for identifying novel therapeutic targets for this condition.

Head and neck squamous cell carcinoma (HNSCC) rank among the most prevalent types of head and neck cancer globally. Unfortunately, a significant number of patients receive their diagnoses at advanced stages, limiting the effectiveness of available treatments. The tumor microenvironment (TME) is a pivotal player in HNSCC development, with macrophages holding a central role. Macrophages demonstrate diverse functions within the TME, both inhibiting and facilitating cancer progression. M1 macrophages are characterized by their phagocytic and immune activities, while M2 macrophages tend to promote inflammation and immunosuppression. Striking a balance between these different polarization states is essential for maintaining overall health, yet in the context of tumors, M2 macrophages typically prevail. Recent efforts have been directed at controlling the polarization states of macrophages, paving the way for novel approaches to cancer treatment. Various drugs and immunotherapies, including innovative treatments based on macrophages like engineering macrophages and CAR-M cell therapy, have been developed. This article provides an overview of the roles played by macrophages in HNSCC, explores potential therapeutic targets and strategies, and presents fresh perspectives on the future of HNSCC treatment.

In observational studies, there exists an association between obesity and epigenetic age as well as telomere length. However, varying and partially conflicting outcomes have notably arisen from distinct studies on this topic. In the present study, two-way Mendelian randomization was used to identify potential causal associations between obesity and epigenetic age and telomeres.

A genome-wide association study was conducted using data from individuals of European ancestry to investigate bidirectional Mendelian randomization (MR) regarding the causal relationships between obesity, as indicated by three obesity indicators (body mass index or BMI, waist circumference adjusted for BMI or WCadjBMI, and waist-to-hip ratio adjusted for BMI or WHRadjBMI), and four epigenetic age measures (HannumAge, HorvathAge, GrimAge, PhenoAge), as well as telomere length. To assess these causal associations, various statistical methods were employed, including Inverse Variance Weighted (IVW), Weighted Median, MR Egger, Weighted Mode, and Simple Mode. To address the issue of multiple testing, we applied the Bonferroni correction. These methods were used to determine whether there is a causal link between obesity and epigenetic age, as well as telomere length, and to explore potential bidirectional relationships. Forest plots and scatter plots were generated to show causal associations between exposures and outcomes. For a comprehensive visualization of the results, leave-one-out sensitivity analysis plots, individual SNP-based forest plots for MR analysis, and funnel plots were included in the presentation of the results.

A strong causal association was identified between obesity and accelerated HannumAge, GrimAge, PhenoAge and telomere length shrinkage. The causal relationship between WCadjBMI and PhenoAge acceleration (OR: 2.099, 95%CI: 1.248-3.531, p = 0.005) was the strongest among them. However, only the p-values for the causal associations of obesity with GrimAge, PhenoAge, and telomere length met the criteria after correction using the Bonferroni multiple test. In the reverse MR analysis, there were statistically significant causal associations between HorvathAge, PhenoAge and GrimAge and BMI, but these associations exhibited lower effect sizes, as indicated by their Odds Ratios (ORs). Notably, sensitivity analysis revealed the robustness of the study results.

The present findings reveal a causal relationship between obesity and the acceleration of epigenetic aging as well as the reduction of telomere length, offering valuable insights for further scientific investigations aimed at developing strategies to mitigate the aging process in humans.

Over the past century, molecular biology's focus has transitioned from proteins to DNA, and now to RNA. Once considered merely a genetic information carrier, RNA is now recognized as both a vital element in early cellular life and a regulator in complex organisms. Long noncoding RNAs (lncRNAs), which are over 200 bases long but do not code for proteins, play roles in gene expression regulation and signal transduction by inducing epigenetic changes or interacting with various proteins and RNAs. These interactions exhibit a range of functions in various cell types, including macrophages. Notably, some macrophage lncRNAs influence the activation of NF-κB, a crucial transcription factor governing immune and inflammatory responses. Macrophage NF-κB is instrumental in the progression of various pathological conditions including sepsis, atherosclerosis, cancer, autoimmune disorders, and hypersensitivity. It orchestrates gene expression related to immune responses, inflammation, cell survival, and proliferation. Consequently, its malfunction is a key contributor to the onset and development of these diseases. This review aims to summarize the function of lncRNAs in regulating NF-κB activity in macrophage activation and inflammation, with a particular emphasis on their relevance to human diseases and their potential as therapeutic targets. The insights gained from studies on macrophage lncRNAs, as discussed in this review, could provide valuable knowledge for the development of treatments for various pathological conditions involving macrophages.

Ambient fine particular matter (PM2.5) exposure has been associated with numerous adverse effects including triggering functional disorders of the placenta and inducing immune imbalance in offspring. However, how maternal PM2.5 exposure impacts immune development during early life is not fully understood. In the current study, we exposed mice with low-, middle-, and high-dose PM2.5 during pregnancy to investigate the potential link between the transcriptional changes in the placenta and immune imbalance in mice offspring induced by PM2.5 exposures. Using flow cytometry, we found that the proportions of B cells, CD3+CD4+ T cells, CD3+CD8+ T cells, and macrophage (Mφ) cells were altered in the blood of PM2.5-exposed mice pups but not dendritic cells (DCs) and natural killer cells (NKs). Using bulk RNA sequencing, we found that PM2.5 exposure altered the transcriptional profile which indicated an inhibition of the complement and coagulation cascades in the placenta. Weighted gene co-expression network analysis (WGCNA) revealed the potential crosstalk between the perturbation of placental gene expression and the changes of immune cell subsets in pups on postnatal day 10 (PND10). Specifically, WGCNA identified a cluster of genes including Defb15, Defb20, Defb25, Cst8, Cst12, and Adam7 that might regulate the core immune cell types in PND10 pups. Although the underlying mechanisms of how maternal PM2.5 exposure induces peripheral lymphocyte disturbance in offspring still remain much unknown, our findings here shed light on the potential role of placental dysfunction in these adverse effects.