The erythroblastic island (EBI) is a multicellular structure defined by the presence of 1 or 2 central macrophages surrounded by at least 3 erythroblasts. EBIs were initially proposed as a specialized microenvironment exclusively for erythroid terminal differentiation. Recent advancements in techniques such as lineage tracing mouse models, imaging flow cytometry, and single-cell RNA sequencing, accumulating evidence has provided novel insights that challenge this conventional view. Notably, the erythropoietin receptor has been identified as a novel marker for EBI macrophages. Additionally, neutrophils have been identified as novel cellular components of EBIs, raising the intriguing hypothesis that EBIs may support other hematopoietic lineage cells as well. Beyond the diverse cellular components of various hematopoietic lineages, even within the erythroid lineage, an immune-prone erythroblast subpopulation has been reported, although it remains unclear whether and how these immune-prone erythroblasts mature in EBIs. These observations indicate that EBIs are a heterogeneous population. In this review, we summarize the most recent findings on EBIs, discuss their potential immune functions, and provide a perspective for future investigations.

Bacterial implant-associated infections predominantly contribute to the failure of prosthesis implantation. The local biofilm microenvironment (BME), characterized by its hyperacidic condition and high hydrogen peroxide (H2O2) level, inhibits the host's immune response, thereby facilitating recurrent infections. Here, a Janus PEGylated CuS nanoparticle (CuPen) armed engineered Lactobacillus casei (L. casei) denoted as LC@CuPen, is proposed to interfere with bacterial metabolism and arouse macrophage antibiofilm function. Once LC@CuPen reached the BME, NIR irradiation-activated mild heat damages L. casei and biofilm structure. Meanwhile, the BME-responsive LC@CuPen can catalyze local H2O2 to produce toxic •OH, whereas in normal tissues, the effect of •OH production is greatly reduced due to the higher pH and lower H2O2 concentration. The released bacteriocin from damaged L. casei can destroy the bacterial membrane to enhance the penetration of •OH into damaged biofilm. Excessive •OH interferes with normal bacterial metabolism, resulting in reduced resistance of bacteria to heat stress. Finally, under the action of mild heat treatment, the bacterial biofilm lysed and died. Furthermore, the pathogen-associated molecular patterns (PAMPs) in LC@CuPen can induce M1 polarization of macrophages through NF-κB pathway and promote the release of inflammatory factors. Inflammatory factors enhance the migration of macrophages to the site of infection and phagocytose bacteria, thereby inhibiting the recurrence of infection. Generally, this engineered L. casei program presents a novel perspective for the treatment of bacterial implant-associated infections and serves as a valuable reference for future clinical applications of engineered probiotics.

Colorectal cancer is a highly prevalent and deadly malignancy worldwide. Current treatment strategies, including surgery, chemotherapy, and targeted therapy, still face limitations due to recurrence and metastasis. By conducting a weighted gene coexpression network analysis on gene expression data from The Cancer Genome Atlas, we pinpointed critical genes linked to M2 macrophages and tumor metastasis. Among these, FOXC1 emerged as a significant prognostic indicator within our predictive model. Clinical sample analysis further confirmed that FOXC1 is upregulated in colorectal cancer tissues and associated with an unfavorable patient outcome. Both in vivo and in vitro experimental results revealed that FOXC1 promotes CRC cell migration, invasion and proliferation by regulating the expression of Snail and TGF-β/Smad2/3 pathways, thereby facilitating the epithelial-mesenchymal transition process. Additionally, FOXC1 recruits M2 macrophages to the tumor microenvironment by regulating CXCL2 expression through Snail. The TGF-β factor secreted by M2 macrophages further activates the TGF-β/Smad2/3 pathway, forming a positive feedback loop. In these processes, FOXC1 plays a critical regulatory role. In summary, this study highlights the critical significance of FOXC1 in CRC progression and indicates its viability as a therapeutic target, offering a novel theoretical foundation for the development of future CRC treatment strategies.

Periodontitis is a chronic inflammatory disorder arising from an imbalance between oral microbiota and the host's immune response, with macrophages as pivotal targets for prevention and treatment. Endosome-associated Trafficking Regulator 1 (ENTR1) is indispensable for protein trafficking and implant osseointegration. However, its specific role in periodontitis has yet to be clarified. This research seeks to explore the effects of ENTR1 on macrophage polarization, elucidate its mechanisms, and evaluate its regulatory functions in the regeneration of periodontal tissues.

A ligature-induced periodontitis mouse model was established to investigate the correlation between macrophage polarization markers and ENTR1 expression. Techniques including qRT-PCR, Western blot, ELISA, flow cytometry, and immunofluorescence staining were utilized to evaluate the impact of ENTR1 on macrophage polarization under inflammatory stimuli. Micro-CT and histological staining were applied to assess periodontal bone resorption. The interaction between ENTR1 and AMP-activated protein kinase (AMPK) was explored through Western blot and co-immunoprecipitation, further validated by applying the AMPK inhibitor Compound C (CpC).

ENTR1 expression was down-regulated in the mice with periodontitis relative to healthy controls. Overexpressing ENTR1 suppressed macrophage M1 polarization and mitigated bone loss in periodontitis, while knocking down ENTR1 exacerbated these effects. ENTR1 directly interacted with AMPK, enhancing its phosphorylation. Furthermore, the inhibitory impact of ENTR1 on macrophage M1 polarization and inflammation-induced alveolar bone resorption were partially attenuated by CpC treatment.

ENTR1 regulates periodontitis by suppressing macrophage M1 polarization through enhancing AMPK phosphorylation, presenting a promising therapeutic target for its prevention and management.

The concept of macrophage polarization has been largely used in human diseases to define a typology of activation of myeloid cells reminiscent of lymphocyte functional subsets. In COVID-19, several studies have investigated myeloid compartment dysregulation and macrophage polarization as an indicator of disease prognosis and monitoring. SARS-CoV-2 induces an in vitro activation state in monocytes and macrophages that does not match the polarization categories in most studies. In COVID-19 patients, monocytes and macrophages are activated but they do not show a polarization profile. Therefore, the investigation of polarization under basic conditions was not relevant to assess monocyte and macrophage activation. The analysis of monocytes and macrophages with high-throughput methods has allowed the identification of new functional subsets in the context of COVID-19. This approach proposes an innovative stratification of myeloid cell activation. These new functional subsets of myeloid cells would be better biomarkers to assess the risk of complications in COVID-19, reserving the concept of polarization for pharmacological programme evaluation. This review reappraises the polarization of monocytes and macrophages in viral infections, particularly in COVID-19.

Acute pancreatitis (AP) is a severe inflammatory condition of the digestive system which, in severe cases, can lead to persistent organ failure (POF). Developing novel therapeutic interventions and diagnostic biomarkers is critical to improve the management and prognosis of this disease. Exosomes, small extracellular vesicles, can reflect the inflammatory state of the pancreas, providing valuable insights into disease progression. Moreover, these vesicles are essential mediators of intercellular communication, modulating inflammatory responses by affecting patterns of cell death and macrophage polarization-key factors in determining AP clinical outcomes. Their stability, bioavailability, and capacity to transport various bioactive molecules render exosomes promising tools for early diagnosis and precision therapy, potentially enhancing patient outcomes. This review highlights the innovative potential of exosomes in transforming the management of AP, providing a foundation for more accurate diagnostics and targeted treatments with clinical applicability.

Osteoarthritis is a chronic and progressive joint disease accompanied by cartilage degeneration and synovial inflammation. It is associated with an imbalance of synovial macrophage M1/M2 ratio tilting more towards the pro-inflammatory M1 than the anti-inflammatory M2. The M1-macrophages rely on aerobic glycolysis for energy whereas the M2-macrophages derive energy from oxidative phosphorylation. Therefore, inhibiting aerobic glycolysis to induce metabolic reprogramming of macrophages and consequently promote the shift from M1 type to M2 type is a therapeutic strategy for osteoarthritis. Here we developed a macrophage-targeting strategy based on opsonization, using nanoparticles self-assembled to incorporate Chrysin (an anti-inflammatory flavonoid) and V-9302 (an inhibitor of glutamine uptake), and the outer layer modified by immunoglobulin IgG by electrostatic adsorption into IgG/Fe-CV NPs. In vitro studies showed that IgG/Fe-CV NPs effectively target M1 macrophages and inhibit HIF-1α and GLUT-1 essential for aerobic glycolysis and promote polarization from M1 to M2-type macrophages. In vivo, IgG/Fe-CV NPs inhibit inflammation and protect against cartilage damage. The metabolic reprogramming strategy with IgG/Fe-CV NPs to shift macrophage polarization from inflammatory to anti-inflammatory phenotype by inhibiting aerobic glycolysis and glutamine delivery may open up new avenues to treat osteoarthritis.

The excessive activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) in macrophages has been recognized as a critical factor in the exacerbation of severe inflammatory bowel disease (IBD). Consequently, the modulation of macrophage NLRP3 activity may serve as an effective strategy for mitigating IBD. Our study has indicated that bicalutamide, a clinically administered agent, has the capacity to reduce inflammation by promoting the degradation of NLRP3 in a macrophage-specific manner. However, the therapeutic efficacy of bicalutamide in treating colitis has remained limited. In an effort to enhance the precision of NLRP3 regulation, a nano-bicalutamide system targeting macrophages has been developed, which has shown potential to significantly improve the therapeutic impact on colitis. Mechanistically, it has been found that this system degrades the NLRP3 protein through the autophagy pathway by recruiting the E3 ligase, mitogen-activated protein kinase kinase 1 (MAP3K1), and the autophagy receptor protein optineurin (OPTN). Furthermore, our findings have indicated that the degradation of macrophage NLRP3 inhibits its M1-type polarization, which in turn hinders the colitis process. The system that we have devised has demonstrated potential to address the urgent need for the treatment of colitis, as well as other diseases related to macrophage NLRP3 dysregulation.

Hepatocellular carcinoma (HCC) is closely linked to alterations in the gut microbiota. This dysbiosis is characterized by significant changes in the microbial population, which correlate with the progression of HCC. Gut dysbiosis ultimately promotes HCC development in several ways: it damages the integrity of the gut-vascular barrier (GVB), alters the tumor microenvironment (TME), and even affects the intratumoral microbiota. Subsequently, intratumoral microbiota present a characteristic profile and play an essential role in HCC progression mainly by causing DNA damage, mediating tumor-related signaling pathways, altering the TME, promoting HCC metastasis, or through other mechanisms. Both gut microbiota and intratumoral microbiota have dual effects on HCC progression; a comprehensive understanding of their complex biological roles will provide a theoretical foundation for potential clinical applications in HCC treatment.

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.

Macrophages play crucial roles in various pathological conditions as well as maintenance of homeostasis. Many chronic inflammatory conditions, such as atherosclerosis, rheumatoid arthritis, and obesity, are known to involve the polarization of macrophages into a proinflammatory state. Therefore, controlling the function of macrophages is a potential strategy to intervene in such pathological conditions. Modulation of immune cell metabolism has recently received attention as a novel therapeutic strategy to counteract such conditions. Recently, a unique nanocapsule (MITO-Porter) that can deliver macromolecules specifically into mitochondria was generated, and its application to improve mitochondrial function was achieved by the direct action of the molecules at the site of the mitochondria in a wide range of cell types but not in immune cells. Therefore, we initiated this study by investigating the feasibility of mitochondria-targeted delivery of coenzyme Q10 (CoQ10), a known antioxidant and cofactor of mitochondrial oxidative phosphorylation, in primary murine bone marrow macrophages (BMDMs) and then evaluated the functional consequences of the treatment with MITO-Porter on mitochondrial function in BMDMs. At steady state, CoQ10-loaded MITO-Porter containing octaarginine (R8) was successfully delivered into the mitochondria, resulting in significant antioxidant effects and increased mitochondrial respiration. Furthermore, the effect of CoQ10 on mitochondrial function in BMDMs was more pronounced when CoQ10 was encapsulated in R8(+) MITO-Porter than when CoQ10 was added alone. This proof-of-concept study highlights the potential of the application of MITO-Porter in macrophages and other immune cells as a novel immunomodulatory therapy for chronic inflammatory conditions.

Tuberculosis (TB) remains one of the most fatal infectious diseases, the pathogenic bacterium Mycobacterium tuberculosis (Mtb) has a thick wall to resist the invasion of extracellular substances and secretes a variety of virulence proteins to antagonize host innate immunity. Rv0222, a protein encoded by the gene Rv0222 in the RD4 region of Mtb, is a critical virulence factor in the pathogenicity of Mtb. However, the mechanism of its regulation of miRNAs during bacterial infection is unclear. We used Rv0222 gene and Mycobacterium smegmatis (M. smegmatis), which is highly homologous to Mtb, to construct Rv0222 recombinant M. smegmatis Ms_Rv0222. Ms_Rv0222 induced down-regulation of miR-9 expression and up-regulation of SIRT1 in RAW264.7 cells and mice post-infection. Up-regulation of SIRT1 caused down-regulation of p65 activity and decreased the expression of pro-inflammatory cytokine, which increased the intracellular survival of M. smegmatis. Si-SIRT1 induced up-regulation of p65 activity and increased the expression of pro-inflammatory cytokine, then decreased the intracellular survival of M. smegmatis. This study reveals that Mtb Rv0222 mediates the suppression of host innate immunity by miR-9 and its target SIRT1, and may provide a potential site for the development of new anti-TB drugs targeting Rv0222.

Cisplatin (DDP) is a key chemotherapeutic agent in the treatment of gastric cancer; however, its efficacy is often limited by chemoresistance, a notable challenge in clinical oncology. The present study aimed to investigate the influence of exosomes derived from M2‑polarized macrophages, which promote this resistance, on the response of gastric cancer cells to DDP, examining both the effects and the underlying mechanisms. M2 macrophages, differentiated from mouse bone marrow cells with interleukin (IL)‑13 and IL‑4, were identified using immunofluorescence staining for CD206 and CD163. Exosomes derived from these macrophages were characterized using transmission electron microscopy and protein markers, including calnexin, tumor susceptibility gene 101 and CD9. The role of exosomal microRNA (miR)‑3681‑3p in DDP resistance was assessed using Cell Counting Kit‑8 and apoptosis assays, while a luciferase reporter assay was used to elucidate the interaction between miR‑3681‑3p and MutL protein homolog 1 (MLH1). Co‑culturing gastric cancer cells with M2 macrophages enhanced DDP resistance, an effect amplified by exosomes from M2 macrophages enriched with miR‑3681‑3p. This microRNA directly targeted and reduced MLH1 protein expression. Overexpression of miR‑3681‑3p through mimic transfection, along with MLH1 silencing by small interfering RNA transfection, significantly increased DDP resistance, as evidenced by elevated IC50 values in AGS cells. By contrast, the overexpression of MLH1 effectively reversed the drug resistance of AGS cells to DDP caused by miR‑3681‑3p mimic transfection, as evidenced by a decrease in the IC50 value. In conclusion, exosomal miR‑3681‑3p from M2 macrophages may have a key role in conferring DDP resistance to gastric cancer by suppressing MLH1, offering a new therapeutic target for overcoming chemoresistance.

With the increasing prevalence of drug-resistant bacterial infections, wound bacterial infections have evolved into an escalating medical problem that poses a threat to the individual health as well as global public health. Traditional drug therapy not only suffers from a single treatment method, low drug utilisation and limited therapeutic effect, but long-term antibiotic abuse has significantly increased bacterial resistance. It is imperative to develop an antibiotic-free biomaterial with antibacterial and anti-inflammatory properties. The current use of photothermal therapy (PTT) and photodynamic therapy (PDT) relies on the generation of massive reactive oxygen species (ROS), which inevitably aggravates the inflammatory response. Herein, we developed AuAg bimetallic nanoparticles based on PDA modification and prepared a novel MoS2-based composite nanomaterials (AuAg@PDA-MoS2 NPs) with multiple mechanisms of antibacterial and anti-inflammatory potentials through the adhesion of PDA. In the early phase, PDT and PTT generated a large amount of ROS for rapid sterilisation. While in the later stage, MoS2 mimicked the peroxidase activity to leverage the ROS, balancing the generation of ROS in the infected environment to achieve the long-term anti-inflammatory. In vitro experiments showed that the killing efficiency of AuAg@PDA-MoS2 NPs was nearly 99 % under the irradiation of 808 nm near-infrared light for 10 min, which demonstrated excellent antibacterial activity. In vivo experiments showed that 808 nm NIR-assisted AuAg@PDA-MoS2 NPs to effectively inhibit infection, alleviated the inflammation, and accelerated the wound healing process. Therefore, AuAg@PDA-MoS2 NPs as a novel biomaterial could achieve programmed antimicrobial and anti-inflammatory effects, which has a promising potential for future application in the treatment of infected wounds.

Common critical size bone defects encountered in clinical practice often result in inadequate bone regeneration,primarily due to the extent of damage surpassing the inherent capacity of the body for self-healing. Bone tissue engineering scaffolds possess the desirable characteristics of biomimetic bone structure, simulated extracellular matrix, optimal mechanical strength, and biological functionality, rendering them the preferred option for the treatment of bone defects. Chitosan demonstrates favorable biocompatibility, plasticity, and a range of biological activities, rendering it a highly appealing material. Chitosan and its derivatives have been found to exert an impact on bone repair through their ability to modulate macrophage polarization, angiogenesis, and the delicate equilibrium of bone remodeling. However, the efficacy of pure chitosan is constrained, necessitating its combination with other bioactive substances to achieve an optimal biomimetic scaffold that is compatible with the specific bone defect site. Chitosan is commonly utilized in the field of bone repair in four different application forms: rigid scaffold, hydrogel, membranes, and microspheres. In order to enhance comprehension of the benefits and constraints associated with chitosan, this review provides a comprehensive overview of the structure and biological properties of chitosan, the molecular mechanisms by which chitosan promotes osteogenic differentiation, the diverse methods of chitosan preparation for various applications, and the impacts of chitosan when loaded with bioactive substances.

Lipid nanoparticles are obtaining significant attention in cancer treatment because of their efficacy at delivering drugs and reducing side effects. These things are like a flexible platform for getting anticancer drugs to the tumor site, especially upon HA modification, a polymer that is known to target tumors overexpressing CD44. HA is promising in cancer therapy because it taregtes tumor cells by binding onto CD44 receptors, which are often upregulated in cancer cells. Lipid nanoparticles are not only beneficial in improving solubility and stability of drugs; they also use the EPR effect, meaning they accumulate more in tumor tissue than in healthy tissue. Adding HA to these nanoparticles expands their biocompatibility and makes them more accurate and specific towards tumor cells. Studies show that HA-modified nanoparticles carrying drugs such as paclitaxel or doxorubicin improve how well cells absorb the drugs, reduce drug resistance, and make tumor shrinking. These nanoparticles can respond to tumor microenvironment stimuli in targeted delivery. This targeted delivery diminishes side effects and improves anti-cancer activity of drugs. Thus, lipid-based nanoparticles conjugated with HA are a promising way to treat cancer by delivering drugs effectively, minimizing side effects, and giving us better therapeutic results.

Delayed tooth extraction socket (TES) healing can cause failure of subsequent oral implantation and increase socioeconomic burden on patients. Excessive amounts of M1 macrophages, apoptotic neutrophils (ANs), and neutrophil extracellular traps (NETs) impair alveolar bone regeneration during TES healing. In the present study, we first discovered that conditioned medium (CM) collected from berberine-treated human bone marrow mesenchymal stem cells (BBR-HB-CM) accelerated TES healing. BBR-HB-CM contained bioactive materials that promoted the polarization of macrophages from M1 to M2, impeded the formation of ANs and NETs, and modulated M2 macrophage efferocytosis in vivo and in vitro. Mechanistically, BBR-HB-CM promoted bone formation by inhibiting macrophage-myofibroblast transition and reprogrammed macrophage polarization through p85/AKT/mTOR pathway-dependent autophagy. The 3-methyladenine abolished the therapeutic effects of BBR-HB-CM. Further studies revealed that BBR-HB-CM accelerated TES healing in rats with type 2 diabetes mellitus. Overall, our results demonstrated that BBR-HB-CM had high potential to promote rapid TES healing.

3D-printed hydrogel scaffolds are widely utilized in auricular cartilage tissue engineering. However, issues such as graft-related inflammation, poor mechanical properties, and the lack of external modulation of 3D-printed scaffolds in vivo have raised significant concerns. To address these challenges, a "fried egg" structure is designed, consisting of chitosan-coated ferroferric oxide magnetic nanoparticles (Fe3O4@CS MNPs), which are uniformly incorporated into hydrogel. Through 4D printing technology, magnetoresponsive hydrogel scaffolds are constructed to overcome the aforementioned limitations. The results demonstrated that, compared to 3D printing, 4D-printed magnetic hydrogel scaffolds significantly enhanced cartilage tissue regeneration in both in vitro and in vivo environments when subjected to an external magnetic field (MF). Furthermore, the mechanical strength of regenerated cartilage approached to that of natural cartilage. The chitosan coating on the surface of MNPs exhibited anti-inflammatory and antibacterial properties, promoting M2 polarization of macrophages and suppressing graft-related inflammation and bacteria. Transcriptomic analysis confirmed that MNPs modulate macrophage immunity by activating JAK2/STAT3 signaling pathway. Taken together, a magnetoresponsive multifunctional scaffold is designed that can be externally controlled by magnetic fields to promote ear cartilage tissue regeneration. The regenerated cartilage exhibits excellent biocompatibility, anti-inflammatory, antibacterial properties, and mechanical performance, providing new insights for auricular cartilage tissue engineering.

Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis. Moreover, although previous studies have reported that the proviral integration of Moloney virus 2 (Pim2) kinase is involved in various cancers through the mediation of aerobic glycolysis in cancer cells, its role in inflammatory arthritis remains unclear. In this study, we demonstrated that multiple metabolic enzymes are activated upon Pim2 upregulation during M1 macrophage polarization. Specifically, Pim2 directly phosphorylates PGK1-S203, PDHA1-S300, and PFKFB2-S466, thereby promoting glycolytic reprogramming. Pim2 expression was elevated in macrophages from patients with inflammatory arthritis and collagen-induced arthritis (CIA) model mice. Conditional knockout of Pim2 in macrophages or administration of the Pim2 inhibitor HJ-PI01 attenuated arthritis development by inhibiting M1 macrophage polarization. Through molecular docking and dynamic simulation, bexarotene was identified as an inhibitor of Pim2 that inhibits glycolysis and downstream M1 macrophage polarization, thereby mitigating the progression of inflammatory arthritis. For targeted treatment, neutrophil membrane-coated bexarotene (Bex)-loaded PLGA-based nanoparticles (NM@NP-Bex) were developed to slow the progression of inflammatory arthritis by suppressing the polarization of M1 macrophages, and these nanoparticles (NPs) exhibited superior therapeutic effects with fewer side effects. Taken together, the results of our study demonstrated that targeting Pim2 inhibition could effectively alleviate inflammatory arthritis via glycolysis inhibition and reversal of the M1/M2 macrophage imbalance. NM@NPs loaded with bexarotene could represent a promising targeted strategy for the treatment of inflammatory arthritis.

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

Regulation of the innate immune response may be an effective strategy to enhance Staphylococcus aureus vaccines. Based on our previous findings that the Listeria peptidoglycan skeleton (pBLP) enhances the immune response through an unknown mechanism, we hypothesized that pBLP provides protection by modulating the innate immune response via trained immunity. In vitro, pBLP increased phagocytosis and inflammatory cytokine levels and elevated the anti-inflammatory cytokine TGF-β following secondary stimulation. In an in vivo model, our findings indicate that pBLP, when administered with a vaccine, protects mice from methicillin-resistant S. aureus challenge and also provides protection against S. aureus CMCC26003 in the absence of antigens. Using an ex vivo model, we demonstrated that pBLP increases markers of trained immunity in peritoneal macrophages. Transcriptome analysis of differentially expressed genes and inhibitor experiments revealed that the trained immunity process induced by pBLP depends on mTOR-HIF-1α and hexokinase 2. This study is the first to demonstrate that pBLP can induce trained immunity. Furthermore, we show that the peptidoglycan skeleton induces a distinct trained immunity phenotype compared to β-glucan, enhancing vaccine protection. Our study provides valuable insights for the design of novel vaccines that integrate both specific and innate immune responses.

Macrophage plays critical roles in immune-related diseases, acting as a crucial therapeutic target for immunotherapy. Rational design and development of effective therapeutics for macrophage reprogramming are still challenging. Here, we rationally engineered polysaccharide nanoadjuvants to reprogram macrophage functions for enhanced immunotherapy in multiple diseases through a macrophage phenotype-specific nanoprobe (MPSNPr)-assisted high-throughput phenotypic screen. This MPSNPr exhibited high macrophage M1 phenotype specificity because of the formation of H-aggregates on the outer surface and the binding to glucose transporter 1 receptors by the polysaccharide nanocarrier. Based on this MPSNPr, a high-throughput platform was constructed and employed to screen a variety of pharmaceuticals for macrophage reprogramming, being able to identify both pro-inflammatory and anti-inflammatory drug candidates. Polysaccharide nanoadjuvants, Dex-BA and Dex-SAL, were rationally engineered with two potent candidates to amplify macrophage reprogramming efficacy both in vitro and in vivo. Dex-BA significantly inhibited tumor growth by inducing macrophage M1 polarization, dendritic cell maturation, and cytotoxic T cell activation in a mice melanoma model. Dex-SAL alleviated rheumatoid arthritis symptoms with reduced inflammation by reprogramming activated macrophages toward anti-inflammatory phenotype. Our work provides a robust strategy for the rational design and development of effective therapeutics for enhanced macrophage-mediated immunotherapy in diverse diseases.

Persistent synovitis is a pivotal pathological feature of rheumatoid arthritis (RA). However, the current rheumatoid drugs are accompanied by severe side effects and have limited anti-inflammatory capabilities. In this work, we designed a bioactive material-folic acid modified layered double hydroxides (FA-LDH), aiming at targeting M1 macrophages and modulating macrophage repolarization. The in vitro experiment showed that FA-LDH mitigated the release of proinflammatory cytokines and promoted the expression of M2 macrophage markers. In terms of the action mechanism, FA-LDH modulated the nucleocytoplasmic transport of the small mothers against decapentaplegic 5 (Smad5) protein by adjusting the pH within the immune microenvironment. Subsequently, relying on the interaction between phospho-Smad5 (pSmad5) and p65, the nuclear factor kappa B signaling pathway was down-regulated through inhibiting nuclear transport of p65. Additionally, FA-LDH exhibited excellent targeting capability toward M1 macrophages and strong accumulation capacity in inflamed joints. In vivo experiment showed that FA-LDH could relieve swelling of limbs, reduce the infiltration of inflammatory cells, and protect joint cartilage and subchondral bone structure in collagen-induced arthritis mice. In summary, this work introduces a strategy for utilizing bioactive FA-LDH in the treatment of RA, highlighting the potential of FA-LDH to alleviate inflammation and reshape the immune microenvironment through the pSmad5/p65 axis.

EARP and GARP complex-interacting protein 1 (EIPR1) may be a new oncogene in tumors, influencing the prognosis and invasion of cancer. However, a systematic analysis of the function of EIPR1 in various cancers remains vacant. Thus, we proceeded with a comprehensive analysis to ascertain the role of EIPR1 among various cancers.

We explored EIPR1 expression in pan-cancer, and its association with clinical stage, survival, gene mutations and methylation by the TIMER 2.0, GEPIA2, cBioPortal, and UALCAN. The protein-protein interaction (PPI) network, immune infiltration, and immune checkpoint assessments of EIPR1 was performed using the STRING and SangerBox. The role of EIPR1 expression in lung adenocarcinoma (LUAD) was explored by the R software. The impact of EIPR1 expression on LUAD progression was studied through in vitro assays.

EIPR1 was overexpressed in most cancers and revealed as a potential prognostic biomarker in tumors, involving in tumorigenesis by affecting its methylation and gene mutations. The immune infiltration and immune checkpoints of tumors were related to the expression of EIPR1. Additionally, EIPR1 expression affected the survival, diagnosis, clinicopathological features, tumor microenvironment, and drug sensitivity of LUAD patients. Validation studies demonstrated that EIPR1 knockdown suppressed the malignant growth, invasion, and migration of LUAD cells.

This study delivers an extensive landscape for the oncogenesis and immunological characteristics of EIPR1, which reveals that EIPR1 may serve as a potential biological target for future prognosis and immune treatment in tumors, especially in LUAD.

Human engineered tissues hold great promise for therapeutic tissue regeneration and repair. Yet, development of these technologies often stalls at the stage of in vivo studies due to the complexity of engineered tissue formulations, which are often composed of diverse cell populations and material elements, along with the tedious nature of in vivo experiments. We introduce a "plug and play" platform called parallelized host apposition for screening tissues in vivo (PHAST). PHAST enables parallelized in vivo testing of 43 three-dimensional microtissues in a single 3D-printed device. Using PHAST, we screen microtissue formations with varying cellular and material components and identify formulations that support vascular graft-host inosculation and engineered liver tissue function in vivo. Our studies reveal that the cellular population(s) that should be included in engineered tissues for optimal in vivo performance is material dependent. PHAST could thus accelerate development of human tissue therapies for clinical regeneration and repair.

Progesterone is an important drug for hormone therapy in uterine endometrial cancer (UEC). However, the therapeutic efficacy of progestogen is often limited by resistance, and the underlying mechanism remains unknown. In this study, we observed heme metabolism is more active in progesterone-insensitive patients. Heme induced macrophages (Mφs) bias towards M2-like phenotype and downregulated the expression of IL-33, resulting in increased levels of Paired box gene 8 (PAX8). Further study showed PAX8 inhibited the transcriptional activity of PGR by binding to the PGR promoter region. In addition, PGR can also act as a transcriptional factor to regulate the transcription of autophagy-related gene 7 (ATG). Low expression of PGR decreases the transcriptional activity of ATG7 promoter, which decreases cell autophagy and promotes the progression of UEC. Overall, this study reveals the important interaction between heme metabolism, IL-33 and PGR in progesterone-insensitive UEC, and is promising to provide new therapeutic targets for overcoming progesterone resistance.

Recent years, immunotherapy has emerged as a pivotal approach in cancer treatment. However, the response of gastric cancer to immunotherapy exhibits significant heterogeneity. Therefore, the early identification of gastric cancer patients who are likely to benefit from immunotherapy and the discovery of novel therapeutic targets are of critical importance.

We collected data from European Nucleotide Archive (ENA) and Gene Expression Omnibus (GEO) databases. In project PRJEB25780, we performed WGCNA analysis and Lasso regression and chose CXCR2P1 for the subsequent analysis. Then, we compared the expression difference of CXCR2P1 among different groups. Kaplan-Meier curve was used to analyze the prognostic value of CXCR2P1, which was validated by project IMvigor210 and GEO datasets. ESTIMATE and CIBERSORT algorithm were used to evaluate the reshaping effect of CXCR2P1 to immune microenvironment of tumor. Differentially expressed genes (DEG) analysis, enrichGO analysis, Gene Set Enrichment Analysis (GSEA) and co-expression analysis were used to explore the cell biological function and signaling pathway involved in CXCR2P1.

WGCNA identified CXCR2P1 as a hub gene significantly associated with immune response to PD-1 inhibitors in gastric cancer. CXCR2P1 expression was elevated in responders and correlated with better prognosis. Functional analysis revealed its role in reshaping the tumor immune microenvironment by promoting immune cell infiltration, including M1 macrophages, activated CD4+ T cells, and follicular helper T cells. CXCR2P1 enhanced antigen presentation via the MHC-II complex, influenced key immune pathways, such as Toll-like receptor signaling and T-cell activation, which led to the up-regulation of expression of PD-L1. GSEA showed CXCR2P1 were correlated with microRNAs. Through DEG analysis and expression analysis, MIR215 was identified as a potential direct target of CXCR2P1.

High expression of CXCR2P1 is correlated with better response to PD-1 inhibitor. It reshapes the immune microenvironment by increasing immune infiltration and changing the fraction of immune cells. In tumor immune microenvironment, CXCR2P1 can promote inflammation, enhance antigen presentation and activate the PD-1/PD-L1-related signaling pathway, which might be achieved by CXCR2P1-MIR215 axis.

The lung as an organ that is fully exposed to the external environment for extended periods, comes into contact with numerous inhaled microorganisms. Lung macrophages are crucial for maintaining lung immunity and operate primarily through signaling pathways such as toll-like receptor 4 and nuclear factor-κB pathways. These macrophages constitute a diverse population with significant plasticity, exhibiting different phenotypes and functions on the basis of their origin, tissue residence, and environmental factors. During lung homeostasis, they are involved in the clearance of inhaled particles, cellular remnants, and even participate in metabolic processes. In disease states, lung macrophages transition from the inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. These distinct phenotypes have varying transcriptional profiles and serve different functions, from combating pathogens to repairing inflammation-induced damage. However, macrophages can also exacerbate lung injury during prolonged inflammation or exposure to antigens. In this review, we delve into the diverse roles of pulmonary macrophages the realms in homeostasis, pneumonia, tuberculosis, and lung tumors.

Osteosarcoma is an aggressive primary malignant bone tumor associated with high rates of metastasis and poor 5-year survival rates with limited improvements in approximately 40 years. Standard multimodality treatment includes chemotherapy and surgery, and survival rates have remained stagnant. Overall, response rates to immunotherapy like immune checkpoint inhibitors have been disappointing in osteosarcoma despite exciting results in other epithelial tumor types. The poor response of osteosarcoma to current immunotherapies is multifactorial, but a key observation is that the tumor microenvironment in osteosarcoma is profoundly immunosuppressive, and increasing evidence suggests a significant role of suppressive myeloid cells in tumor progression and immune evasion, particularly by myeloid-derived suppressor cells. Targeting suppressive myeloid cells via novel agents are attractive strategies to develop novel immunotherapies for osteosarcoma, and combination strategies will likely be important for durable responses. In this review, we will examine mechanisms of the immunosuppressive microenvironment, highlight pre-clinical and clinical data of combination strategies including colony-stimulating factor 1 (CSF-1) receptor, phosphoinositide 3-kinase (PI3K), CXCR4, and checkpoint inhibition, as well as the role of canine models in elucidating myeloid cells as targets in osteosarcoma immunotherapy.

Lacticaseibacillus rhamnosus CRL1505 and Lactiplantibacillus plantarum CRL1506 increase the resistance of mice to Gram-negative pathogens infections. In this work, we advanced the characterization of the CRL1505 and CRL1506 immunomodulatory properties by evaluating their effect on the Toll-like receptor 4 (TLR4)-triggered immune response in macrophages. We performed experiments in murine RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS) to evaluate the transcriptomic changes induced by lactobacilli. These in vitro experiments were complemented with in vivo studies in mice to determine the effect of CRL1505 and CRL1506 strains on Peyer's patches and peritoneal macrophages. Microarray transcriptomic studies and qPCR confirmation showed that the CRL1505 and CRL1506 strains modulated the expression of inflammatory cytokines and chemokines as well as adhesion molecules in LPS-challenged RAW macrophages, making the effect of L. rhamnosus CRL1505 more remarkable. Lactobacilli also modulate regulatory factors in macrophages. L. plantarum CRL1506 increased il10 and socs2 while L. rhamnosus CRL1505 upregulated il27, socs1, and socs3 in RAW cells, indicating a strain-specific effect. However, in vivo, both strains induced similar effects. Peyer's patches and peritoneal macrophages from mice treated with lactobacilli produced higher levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-6, and colony stimulating factor (CSF)-3 after LPS stimulation. This effect would allow improved protection against pathogens. In addition, both lactobacilli equally modulated socs1 and socs2 expressions and IL-10 and IL-27 production in Peyer's patches macrophages and socs3 and IL-10 in peritoneal cells. Furthermore, lactobacilli reduced the production of IL-1β, IL-12, CSF2, C-C motif chemokine ligand (CCL)-2, and CCL8 in LPS-challenged macrophages. This differential modulation of regulatory and inflammatory factors would allow minimal inflammatory-mediated tissue damage during the generation of the innate immune response. This work provides evidence that L. rhamnosus CRL1505 and L. plantarum CRL1506 modulate macrophages' TLR4-mediated immunotranscriptomic response, helping to improve protection against Gram-negative bacterial infections.

The immunomodulatory effects of seminal plasma (SP) on the maternal immune system play an important role in the implantation and development of the embryo. Decidual macrophages (dMΦs) are one of the major immune cells in the maternal-fetal immune microenvironment, and their M2-type polarization facilitates the establishment and maintenance of pregnancy. However, the role of SP on the polarization of dMΦs is unknown. In this study, we investigated the role and mechanism of SP on the polarization of dMΦs by gene chip sequencing as well as in vitro and in vivo experiments. The results revealed that SP promoted dMΦs M2-type polarization. Gene chip sequencing revealed that miR-26-5p was highly expressed in seminal exosomes (SEs) which could act on PTEN/PI3K/AKT signaling pathway and significantly promote MΦs M2 polarization. Moreover, SEs supplementation significantly reduced embryo resorption in spontaneously aborted mice. In conclusion, our study demonstrated that the SEs derived miR-26-5p in SP promoted the M2 polarization of dMΦs by targeting PTEN/PI3K/AKT signaling pathway, which created an immune-tolerant environment conducive to embryo implantation and development. This study provided new ideas for clinical SP-assisted therapy to improve pregnancy outcomes.

Pathological new bone formation is the main cause of disability in ankylosing spondylitis (AS), and so far, it lacks a targeted therapy. Macrophages are central orchestrators of inflammation progression and tissue remodeling, but their contribution to pathological new bone formation has largely not been explored. Here, it is identified that TREM2+ macrophages predominated within the sites of new bone formation and adjacent to osteogenic precursor cells. In vivo, both depletion of macrophages and knockout of Trem2 significantly reduced pathological new bone formation in a collagen antibody-induced arthritis (CAIA) model. Specifically, TREM2+ macrophages promoted osteogenic differentiation of ligament-derived progenitor cells (LDPCs) by secreting CREG1, a secretory glycoprotein involved in cell differentiation and normal physiology. CREG1-IGF2R-PI3K-AKT signaling pathway is involved in TREM2+ macrophage-mediated pathological new bone formation. In addition, it is found that IL-33 promoted TREM2+ macrophage differentiation through phosphorylation of STAT6. Targeting the above signalings alleviated new bone formation in the CAIA model. The findings highlight the critical role of IL-33-induced TREM2+ macrophages in pathological new bone formation and provide potential therapeutic targets for halting spinal ankylosis in AS.

Aging naturally involves a decline in biological functions, often triggering a disequilibrium of physiological processes. A common outcome is the altered response exerted by the immune system to counteract infections, known as immunosenescence, which has been recognized as a primary cause, among others, of the so-called long-COVID syndrome. Moreover, the uncontrolled immunoreaction leads to a state of subacute, chronic inflammatory state known as inflammaging, responsible in turn for the chronicization of concomitant pathologies in a self-sustaining process. Anti-inflammatory and immunosuppressant drugs are the current choice for the therapy of inflammaging in post-COVID complications, with contrasting results. The increasing knowledge of the biochemical pathways of inflammaging led to disclose new small molecules-based therapies directed toward different biological targets involved in inflammation, immunological response, and oxidative stress. Herein, paying particular attention to recent clinical data and preclinical literature, we focus on the role of endocannabinoid system in inflammaging, and the promising therapeutic option represented by the CB2R agonists, the role of novel ligands of the formyl peptide receptor 2 and ultimately the potential of newly discovered monoamine oxidase (MAO) inhibitors with neuroprotective activity in the treatment of immunosenescence.

M2 macrophages (M2 cells) are known to be involved in both Th2 responses and immune regulation. However, the underlying mechanisms remain unclear. Functional abnormalities in macrophages are associated with airway allergy (AA). The objective of this study was to investigate the role of methyltransferase-like 5 (Mettl5) in macrophages and its potential to alleviate AA. In this study, an airway allergy (AA) mouse model was established using dust mite extracts (DME) as the specific antigen. M2 cells were collected from mice with and without AA. The role of Mettl5 in modulating the immune activities of M2 cells was assessed using both epigenetic and immunological approaches. We found that Mettl5 levels were elevated in airway M2 cells from mice with AA. The presence of Mettl5 in airway M2 cells was positively correlated with airway Th2 polarization in these mice. Airway M2 cells from AA mice exhibited impaired immune-suppressive function, which was resolved by ablating the Mettl5 gene in macrophages. Mettl5 was responsible for the hypermethylation of the Il10 promoter in airway M2 cells of AA mice. Exposure to DME induced Mettl5, which in turn recruited USP21 to deubiquitinate GATA3, thereby boosting IL-4 expression in M2 cells. Inhibiting Mettl5 restored the immune-suppressive capacity of airway M2 cells and mitigated experimental AA. In conclusion, Mettl5 plays a critical role in subverting the immune-regulatory capacity and enhancing IL-4 expression in M2 cells. Inhibition of Mettl5 can mitigate experimental AA by restoring the immune-regulatory functions of M2 cells.

Lung adenocarcinoma (LUAD) is responsible for majority cases of lung cancer and considered to be the primary cause of cancer-related mortality. The imbalance of cellular proliferation and apoptosis is critically implicated in the pathogenesis and progression of LUAD. Sphingomyelin, a vital lipid component, is integral to the regulation of tumor cell growth and apoptosis, and has garnered significant attention as a target in novel anticancer therapies. The pivotal molecules involved in sphingomyelin metabolism are crucial in modulating tumor cell behavior, thereby influencing clinical outcomes.

A comprehensive consensus clustering analysis was conducted by collecting clinical LUAD figures from the TCGA and GEO databases. By employing Cox regression and Lasso regression analysis, a prognostic model for LUAD patients was established by identifying seven sphingolipid-related genes (SRGs), and validated in the GEO database. The study also delved into the clinical relevance, functional capabilities, and immune implications of prognostic signals associated with sphingolipid metabolism. Finally, experiments conducted in vitro confirmed the imbalance of sphingolipid-associated genes in LUAD.

Using the prognostic model, lung adenocarcinoma (LUAD) patients can be divided into high-risk and low-risk groups. Meanwhile, we can observe marked disparities in survival times among these groups. Additionally, the model demonstrates high predictive accuracy in external validation cohorts. Research on the immune microenvironment and immunotherapy points to this risk stratification as a useful reference for immunotherapeutic strategies in LUAD. Finally, our hypothesis was corroborated through in vitro experiments.

This study demonstrates that sphingolipid-related gene prognostic characteristics correlate with tumor progression and recurrence, long-term prognosis, and immune infiltration in LUAD patients. The outcomes of our study could help shape innovative strategies for early intervention and prognosis prediction in lung adenocarcinoma.

Radiation induced lung injury, known as the main complication of thoracic radiation, remains to be a major resistance to tumor treatment. Based on the recent studies on radiation-induced lung injury, this review collated the possible mechanisms at the level of target cells and key pathways, corresponding prognostic models including predictors, patient size, number of centers, radiotherapy technology, construction methods and accuracy, and pharmacotherapy including drugs, targets, therapeutic effects, impact on anti-tumor treatment and research types. The research priorities and limitations are summarized to provide a reference for the research and management of radiation-induced lung injury.

Osteosarcoma (OS) is one of the most prevalent bone malignancies with a poor prognosis. Various types of programmed cell death patterns can influence cancer progression and response to treatment. We aimed to integrate different molecular characteristics of cell death for risk stratification and personalized therapy. First, we obtained transcriptomic, single-cell transcriptomic, and clinical information from the TARGET-OS and GEO databases as well as analyzed genes in fourteen cell death patterns to establish the cell death index (CDI) signature. A nomogram constructed from the CDI calculated from seven genes in combination with metastasis could effectively predict the prognosis of OS patients. Subsequently, the prognostic value and immune characteristics in CDI-defined subgroups were analyzed. A construct nomogram model was also constructed with clinical information. Notably, immunohistochemistry confirmed that the expression of GALNT14, a core gene in CDI model, correlated with poor survival. Deficiency of the highly expressed prognostic gene GALNT14 significantly repressed OS progression and OS cell proliferation by promoting apoptosis. We subsequently demonstrated that Bortezomib, a targeted inhibitor of GALNT14, can be used to enhance chemosensitivity. Finally, it was further elucidated that Bortezomib reduces MT2A glycosylation and improves its stability to promote apoptosis in OS cells by inhibiting GALNT14 expression. In summary, integration of multiple cell death genes may improve the ability to stratify risk in patients with OS, and targeting GALNT14 with Bortezomib improves chemotherapy sensitivity and induces apoptosis.