Cisplatin is a platinum-based drug that is frequently used to treat multiple tumors. The anti-tumor effect of cisplatin is closely related to the tumor immune microenvironment (TIME), which includes several immune cell types, such as the tumor-associated macrophages (TAMs), cytotoxic T-lymphocytes (CTLs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and natural killer (NK) cells. The interaction between these immune cells can promote tumor survival and chemoresistance, and decrease the efficacy of cisplatin monotherapy. Therefore, various combination treatment strategies have been devised to enhance patient responsiveness to cisplatin therapy. Cisplatin can augment anti-tumor immune responses in combination with immune checkpoint blockers (such as PD-1/PD-L1 or CTLA4 inhibitors), lipid metabolism disruptors (like FASN inhibitors and SCD inhibitors) and nanoparticles (NPs), resulting in better outcomes. Exploring the interaction between cisplatin and the TIME will help identify potential therapeutic targets for improving the treatment outcomes in cancer patients.

Purpose: Human amniotic fluid stem cells (hAFSCs) have shown significant regenerative potential in treating hair loss, wound healing, and tissue repair. This study aims to evaluate the effects of human amniotic fluid (hAF) on hair follicle (HF) regeneration and immune system modulation.

Materials and Methods: The hAF used was pooled, acellular, and gamma-irradiated to standardize its contents and enhance its stability. Both irradiated (FAFI) and non-irradiated (FAF) hAF were assessed for their efficacy and safety in promoting hair growth and modulating immune responses in a rat model of hair loss. The study examined HF regeneration, transition to the anagen phase, and macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype.

Results: Both FAF and FAFI treatments significantly increased HF density, with FAFI exhibiting enhanced effects. Histological analysis demonstrated improved HF regeneration, increased M2 macrophages, and reduced collagen fiber deposition in treated areas. Gamma irradiation likely improved the efficacy of FAFI by stabilizing active components and inhibiting protease activity.

Conclusions: Irradiated hAF is a safe and effective therapeutic candidate for alopecia and HF growth disorders. These findings support further evaluation of hAF in clinical trials to validate its potential for hair regeneration therapies.

Rheumatoid arthritis (RA) is an inflammatory immune-triggered disease that causes synovitis, cartilage degradation, and joint injury. In nanotechnology, conventional liposomes were extensively investigated for RA. However, they frequently undergo rapid clearance, reducing circulation time and therapeutic efficacy. Additionally, their stability in the bloodstream is often compromised, resulting in premature drug release. The current review explores the potential of targeted liposomal-based nanosystems in the treatment of RA. It highlights the pathophysiology of RA, explores selective targeting sites, and elucidates diverse mechanisms of novel liposomal types and their applications. Furthermore, the targeting strategies of pH-sensitive, flexible, surface-modified, PEGylated, acoustic, ROS-mediated, and biofunctionalized liposomes are addressed. Targeted nanoliposomes showed potential in precisely delivering drugs to CD44, SR-A, FR-β, FLS, and toll-like receptors through the high affinity of ligands. In vitro studies interpreted stable release profiles and improved stability. Ex vivo studies on skin demonstrated that ultradeformable and glycerol-conjugated liposomes enhanced drug penetrability. In vivo experiments for liposomal types in the arthritis rat model depicted remarkable efficacy in reducing joint swelling, pro-inflammatory cytokines, and synovial hyperplasia. In conclusion, these targeted liposomes represented a significant leap forward in drug delivery, offering effective therapeutic options for RA. In the future, integrating these advanced liposomes with artificial intelligence, immunotherapy, and precision medicine holds great promise.

Tendinopathy is a common musculoskeletal disorder in which a significant number of patients do not attain effective therapeutic outcomes. The extent of the inflammatory response and the dynamics of collagen synthesis metabolism are critical factors that influence the intrinsic self-repair capacity of tendons. However, the poor microenvironment within the tendon significantly impedes the self-repair process in tendinopathy. In this study, an injectable tendon-derived decellularized extracellular matrix (tdECM) hydrogel was utilized to treat tendinopathy. This hydrogel provides a more cytocompatible microenvironment while retaining certain bioactive factors of native tendon extracellular matrix (ECM), compared to collagen hydrogel. Notably, it was discovered for the first time that the tdECM hydrogel promotes M2 macrophage polarization, thereby exerting an anti-inflammatory effect in vivo. Furthermore, utilizing tdECM as a carrier for the sustained release of tendon-derived stem cells exosomes (TDSCs-Exos), our findings from both in vitro and in vivo studies indicate that the tdECM hydrogel, in conjunction with exosomes, demonstrated a pronounced synergistic enhancement in modulating inflammation, promoting M2 macrophage polarization, and facilitating tendon regeneration and repair efficacy. These results suggest its potential as a promising therapeutic strategy for tendon disorders.

Hyperuricemia is a metabolic disorder primarily associated with gout and implicated in various metabolic inflammatory diseases. While the role of monosodium urate crystals triggering inflammation has been well-documented, recent findings suggest that soluble high uric acid (HUA) also induces pro-inflammatory cytokine production in human monocytes. However, the comprehensive effects of HUA levels on macrophage dysfunction and the underlying mechanisms remain underexplored. This study employs urate oxidase knockout (UOX-KO) and receptor for advanced glycation end products deficiency (RAGE-/-) mouse models to elucidate macrophage function and its mechanistic pathways. Our results demonstrate that HUA promotes M1 polarization and migration of macrophages while impairing their phagocytic ability. This process is mediated through the high mobility group box 1 (HMGB1)-RAGE- ROS axis. Notably, RAGE deficiency in bone marrow-derived cells partially mediates these effects. Pathologically, elevated HMGB1 and monocyte chemoattractant protein 1 levels in pancreatic islets increases macrophage infiltration in UOX-KO mice. Treatment with the FPS-ZM1, as a pharmacological RAGE inhibitor, effectively decreases serum UA levels, ameliorates islet inflammation and insulin resistance. These findings suggest that soluble HUA serves as a pro-inflammatory trigger through the HMGB1-RAGE-ROS axis, and that RAGE inhibition may mitigate these effects by decreasing inflammatory macrophage infiltration in the islets. Additionally, the influence of UA on macrophages extends beyond gout, potentially contributing to the pathogenesis of other metabolic inflammatory conditions, such as atherosclerosis, non-alcoholic steatohepatitis, obesity, and hyperlipidemia.

Multidrug-resistant organisms (MDRO), including MDR Enterobacter cloacae, may emerge due to the extensive usage of antibiotics and threaten the lives of millions of people around the world. Developing new antibiotic-free strategies to combat E. cloacae infections and curb the spread of drug-resistant genes is crucial. Bacteriophage therapy has garnered widespread attention as a promising approach to tackle bacterial infections. Herein, we isolated a specific bacteriophage (vB_Ent31) targeting E. cloacae from sewage using E. cloacae Ent31 as the host bacterium. vB_Ent31 is a tadpole-like phage with double-stranded DNA belonging to the Siphoviridae family. It exhibits narrow-spectrum activity against Enterobacter spp. and remains stable across a temperature range of 4-50 °C and pH 4 to 11. Significantly, vB_Ent31 prevents proliferation of Ent31 and inhibits inflammation, which further accelerate wound healing. Our findings suggest that bacteriophage therapy could offer an alternative to combating drug-resistant bacteria.

To examine if a novel antimicrobial silane K21 can alter macrophage polarisation and affect fibroblast proliferation by deciphering the molecular pathways for programmed healing using a combined in vitro and in vivo (animal) burn model.

An injectable silane-based antimicrobial aimed to modulate macrophage polarisation was manufactured. Experimental analysis included colorimetric cell migration assays on gingival fibroblasts, macrophage phagocytosis characterisation, immunofluorescence staining, triacylglycerol accumulation within macrophages by LCMS, cellular metabolic/proliferation assays, macrophage exposure quantification with morphology assessment using FE-SEM, Raman spectral analysis, RNA isolation for relative gene expression and animal study model to morphometrically and microscopically analyse partial thickness burn wound healing under QAS/K21.

M1 and M2 polarisation both appeared exaggerated under QAS/K21 treatment. The wounds treated with K21 had depicted accelerated healing as compared to control (P < .05) in dorsal skin of rabbits. Relative gene expression results demonstrate reduced cytokine and anti-inflammatory response under the influence of K21. While M1 expression, TG accumulation, and associated characterisations demonstrate the programmed inflammatory potential of K21.

the antimicrobial and reparative efficacy of K21 silane aids in programmed inflammation for enhanced tissue healing and repair.

M2 macrophage-derived exosomes have been identified to modulate hepatocellular carcinoma (HCC) progression. E-twenty-six (ETS) variant transcription factor 4 (ETV4) shows protumoral effects in HCC. Here, we aimed to probe whether ETV4 performed oncogenic effects on HCC by macrophage-derived exosomes and its associated mechanism.

Exosomes were isolated from macrophages and co-cultured with HCC cells. qRT-PCR and western blotting were utilised for the detection of mRNA and protein. Cell survival was evaluated using EdU assay and flow cytometry. Glycolysis was determined by measuring the glucose uptake, lactate production, and ATP levels. Cell stemness was assessed by sphere formation and flow cytometry. The interaction between ETV4 and SULT2B1 (sulfotransferase family 2B member 1) was determined by a dual-luciferase reporter and chromatin immunoprecipitation assays. In vivo assay was performed by establishing mouse xenograft models.

ETV4 was highly expressed in the exosomes of M2 macrophages and could be internalised by HCC cells. ETV4 derived from M2 macrophage exosomes promoted HCC cell proliferation, glycolysis and stemness in vitro, and enhanced HCC growth in nude mice. Mechanistically, ETV4 interacted with SULT2B1 and promoted it transcription. SULT2B1 silencing suppressed HCC cell proliferation, glycolysis and stemness. In addition, exosomal ETV4 derived from M2 macrophage performed its effects by modulating SULT2B1.

ETV4 derived from M2 macrophage exosomes promoted HCC cell proliferation, glycolysis and stemness by interacting with SULT2B1, suggesting a novel insight into developing exosome-based therapy for HCC.

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

Studies have shown that the colonisation of active microorganisms is more conducive to the development of tumour immunotherapy, but intuitive evidence regarding shaping of the tumour immune microenvironment is lacking. In this study, we used Bifidobacterium longum subsp. longum (XZ01) to intervene in a colon cancer mouse model and found that its mechanism may be related to the interaction between the spatial distribution of microorganisms and tumour immunity. Through the visualisation method we established, for the first time, we showed that harmful active bacteria such as Streptococcus and Rhodococcus specifically accumulate in the middle and upper layers of tumour tissue. These bacteria likely participate in signalling pathways that affect macrophages by directly contacting or invading the macrophages, leading to a nondifferentiated state in macrophages and the loss of some immune functions. Furthermore, the accumulation of Streptococcus and Rhodococcus fragments in the deep layer of tumour tissue likely upregulates the expression of IL-10 in tumour tissue and inhibits other immune cells, such as CD8+ T cells, DC and NK cells. In contrast, XZ01 can specifically compete for the growth sites of Streptococcus and Rhodococcus in the middle and upper layers of tumour tissue and probably protects macrophages from being invaded by harmful bacteria. XZ01 directly regulates the polarisation of M0 macrophages towards the M1 phenotype by upregulating IFN-γ, thus activating tumour immunity to inhibit the growth of tumour cells. This study revealed that the influence of active microorganisms on the tumour immune microenvironment is crucial for effective immunotherapy intervention, potentially offering new targets for improving patient prognosis.

Obstetric antiphospholipid syndrome (OAPS) is a pregnancy-related complication characterized by trophoblast pyroptosis and placental injury induced by antiphospholipid antibodies (aPLs). M2-polarized macrophage-derived exosomes (M2-exos) exert anti-inflammatory, immunomodulatory, and growth-promoting effects in various autoimmune diseases and tumors. However, their role in OAPS is not yet clear. Therefore, in this study, we isolated M2-exos from M2 macrophages and investigated their effects on trophoblast proliferation, death, migration, invasion, and pyroptosis following stimulation using aPLs.

First, we established an animal model of OAPS and thereafter treated the OAPS mice with exogenous M2-exos via injection through the tail vein. Then to clarify the roles of miR-20a-5p and thioredoxin-interacting protein (TXNIP) in OAPS, we performed gain- or loss-of-function assays, and used GraphPad Prism software to analyze the collected data with statistical significance set at P < 0.05.

MicroRNAs (miRNAs) sequencing revealed the enrichment of miR-20a-5p in M2-exos, and these M2-exos significantly alleviated aPLs-induced trophoblast dysfunction. Our results also indicated that M2-exos delivered miR-20a-5p to trophoblast cells directly targeted thioredoxin-interacting protein (TXNIP), and thus suppressed the TXNIP/NLRP3 pathway, reduced pyroptosis and inflammation in trophoblast cells, and improved placental function and fetal development.

M2-exos improve pregnancy outcomes in OAPS via the miR-20a-5p/TXNIP/NLRP3 axis, and thus represent as a novel therapeutic approach for aPLs-induced OAPS.

Liver fibrosis is caused by liver injury resulting from the wound healing response. According to recent research, the primary factor responsible for liver fibrosis is the activation of hepatic stellate cells (HSCs). C-C motif chemokine ligand 1 (CCL1) is one of several chemokine genes clustered on chromosome 17, which is involved in immune regulation and inflammatory processes. However, the role of CCL1 in liver fibrosis has not been reported. We found that CCL1 secreted by macrophages can target and activate the receptor protein C-C motif chemokine receptor 8 (CCR8) of HSCs, accelerating liver fibrosis progression by activating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway. This suggested that the CCL1-mediated regulation of CCR8 is an important event in liver fibrosis progression. In conclusion, this study identified a novel signalling axis, the CCL1/CCR8/JAK/STAT pathway, which regulates the activation and apoptosis of HSCs, thus providing a novel therapeutic strategy for liver fibrosis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by excessive inflammation, pathological bone resorption, and systemic osteoporosis. It lacks effective treatment due to the complex pathogenesis. Gene therapy, especially targeted oligonucleotide (ON) delivery therapy, offers a new prospect for the precise treatment of RA. Nevertheless, the clinical application of ON delivery therapy still faces various challenges such as the rapid enzymolysis by RNAse, the lack of tissue targeting ability, difficulty in cell membrane penetration, and the incapability of endolysosomal escape. To address these issues, a novel kind of engineered peptide and oligonucleotide (PON) nanohybrids are designed and fabricated, which provide various advantages including good biosafety, inflammatory region-targeted delivery, cell membrane penetration, reactive oxygen species (ROS) scavenging, and endolysosomal escape. The PON nanohybrids produce promising effects in suppressing inflammatory responses and osteoclastogenesis of macrophages via multiple signaling pathways. In vivo administration of PON nanohybrids not only ameliorates local joint bone destruction and systemic osteoporosis in the pathological state, but also demonstrates good prophylactic effects against the rapid progression of RA disease. In conclusion, the study presents a promising strategy for precise RA treatment and broadens the biomedical applications of gene therapy based on delivery system.

Immune checkpoint inhibitors (ICIs)-induced cardiac injury is a life-threatening immune-related adverse events (irAEs). However, the current understanding of its pathogenesis and therapeutic options is relatively limited. We aimed to provide a comprehensive overview of the myocardial inflammatory injury process and underlying mechanisms associated with ICIs.

We conducted a descriptive analysis of lung cancer patients with ICIs-induced myocarditis at our institution and validated our clinical findings using single-cell sequencing (scRNA-seq) data. Furthermore, we established animal and cellular models to investigate the underlying mechanisms.

Our findings revealed that lung cancer patients with ICIs-induced myocarditis exhibit an early increase in peripheral blood monocytes, which migrate to the heart and differentiate into macrophages, ultimately leading to myocardial inflammation. Mechanistically, programmed death-1 (PD-1) inhibition triggers myocardial inflammation through the activation of the signal transducer and activator of transcription 1 (STAT1)/nuclear factor kappa-B (NF-κB)/oligomerization domain (NOD)-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling pathway and drives the polarization of macrophages towards the M1 phenotype. However, the ubiquitin (Ub)-autophagy pathway degrades NLRP3 inflammasomes, resulting in the gradual resolution of inflammation and the transition of M1 macrophages to the M2 phenotype. Finally, mouse experiments confirmed that NLRP3 inhibition using MCC950 effectively alleviates myocardial inflammatory injury.

We recommend monitoring fluctuations in peripheral blood monocyte counts in lung cancer patients undergoing ICIs treatment. Additionally, MCC950 holds potential as a therapeutic agent for ICIs-induced cardiac inflammation injury.

Bioadhesives have found significant use in medicine and engineering, particularly for wound care, tissue engineering, and surgical applications. Compared to traditional wound closure methods such as sutures and staples, bioadhesives offer advantages, including reduced tissue damage, enhanced healing, and ease of implementation. Recent progress highlights the synergy of bioadhesives and immunoengineering strategies, leading to immunomodulatory bioadhesives capable of modulating immune responses at local sites where bioadhesives are applied. They foster favorable therapeutic outcomes such as reduced inflammation in wounds and implants or enhanced local immune responses to improve cancer therapy efficacy. The dual functionalities of bioadhesion and immunomodulation benefit wound management, tissue regeneration, implantable medical devices, and post-surgical cancer management. This review delves into the interplay between bioadhesion and immunomodulation, highlighting the mechanobiological coupling involved. Key areas of focus include the modulation of immune responses through chemical and physical strategies, as well as the application of these bioadhesives in wound healing and cancer treatment. Discussed are remaining challenges such as achieving long-term stability and effectiveness, necessitating further research to fully harness the clinical potential of immunomodulatory bioadhesives.

Sepsis is a systemic inflammatory response syndrome triggered by the invasion of bacteria or pathogenic microorganisms into the human body, which may lead to a variety of serious complications and pose a serious threat to the patient's life and health. Liquid-liquid phase separation (LLPS) is a biomolecular process in which different biomolecules, such as proteins and nucleic acids, form liquid condensates through interactions, and these condensates play key roles in cellular physiological processes. LLPS may affect the development of sepsis through several pathways, such as modulation of inflammatory factors, immune responses, and cell death, by altering the function or activity of biomolecules, which, in turn, affect the cellular response to infection and inflammation. In this paper, we first discuss the mechanism of phase separation, then summarize the studies of LLPS in sepsis, and finally propose the potential application of LLPS in sepsis treatment strategies, while pointing out the limitations of the existing studies and the directions for future research.

SPP1+ macrophages, characterized by elevated expression of the osteopontin gene (secreted phosphoprotein 1, SPP1), have emerged as key players in various pathological contexts, including aging, chronic inflammatory diseases, and cancer. While frequently classified as a subclass of tumor-associated macrophages in oncological settings, their presence in noncancer conditions, such as aging-related disorders and muscular diseases, suggests a broader role beyond tumors. These macrophages share conserved traits, including fibrosis promotion, extracellular matrix remodeling, and immune modulation, often linked to poor clinical outcomes. This perspective explores the multifaceted roles of SPP1+ macrophages across diseases and advocates for their reclassification as a distinct macrophage subtype associated with chronic or prolonged inflammation. Recognizing their cross-disease relevance could reshape macrophage biology and inform targeted therapeutic strategies.

The precise molecular mechanisms through which neutrophils regulate macrophages in the progression and resolution of acute inflammation remain poorly understood. Here, we present new findings on the role of Dicer in regulating macrophage phenotypic transitions essential for proper inflammatory progression and resolution, influenced by neutrophils. Using a zymosan A (Zym A)-induced self-limited mouse peritonitis model, we observed that Dicer expression in macrophages was significantly reduced by neutrophil-derived IFN-γ during the progression phase, but gradually returned to normal levels during the resolution phase following the engulfment of apoptotic neutrophils. Our study on macrophage-specific Dicer1-depletion (Dicer1-CKO) mice demonstrated that inflammation in these mice was more severe during the progression phase, characterized by increased pro-inflammatory cytokines and enhanced neutrophil trafficking. Additionally, resolution was impaired in Dicer1-CKO mice, leading to the accumulation of uncleared apoptotic neutrophils. Specifically, the absence of Dicer in macrophages resulted in M1 polarization and heightened bactericidal activity, facilitating the progression of acute inflammation. Conversely, inducing Dicer expression promoted macrophage transition to M2 polarization, enhancing apoptotic cell clearance and expediting the resolution of inflammation. Our findings suggest that Dicer plays a central role in regulating the progression and resolution of acute inflammation, with implications for the treatment of inflammatory diseases.

Under homeostatic conditions, haematopoiesis in Drosophila larvae occurs in the lymph gland and sessile haemocyte clusters to produce two functionally and morphologically different cells: plasmatocytes and crystal cells. It is well-established that in the lymph gland both cell types stem from a binary decision of the medullary prohaemocyte precursors. However, in sessile clusters and dorsal vessel, crystal cells have been shown to originate from the transdifferentiation of plasmatocytes in a Notch/Serrate-dependent manner. We show that transdifferentiation occurs also in the lymph gland. In vivo phagocytosis assays confirm that cortical plasmatocytes are functionally differentiated phagocytic cells. We uncover a double-positive population in the cortical zone that lineage-tracing and long-term live imaging experiments show will differentiate into crystal cells. The reduction of Notch levels within the lymph gland plasmatocyte population reduces crystal cell number. This extension of a transdifferentiation mechanism reinforces the growing role of haematopoietic plasticity in maintaining homeostasis in Drosophila and vertebrate systems. Future work should test the regulation and relative contribution of these two processes under different immunological and/or metabolic conditions.

NF-κB, a multifunctional transcription factor, is linked to cancer initiation and progression. As a key immune mediator, it may play a crucial role in HPV-induced cervical carcinogenesis. However, consensus is lacking on the activation timing of NF-κB during the transition from cervical intraepithelial neoplasia (CIN) to cervical squamous cell carcinoma (CSCC). In this study, immunohistochemical analysis was performed to examine RELA, one of the important members of the NF-κB family, and phospho-RELA expression in different cervical lesions. Then, we analyzed NF-κB regulation of differentially expressed genes (DEGs) in cervical lesions vs. normal tissues. Gene enrichment identified oncogenic DEGs, followed by expression and survival analyses. The impact of NF-κB activation on cervical cell proliferation, migration, and oncogenic regulation, as well as the effects of inhibiting NF-κB, were examined. Our study showed that NF-κB activation starts in cervical simple hyperplasia and intensifies as CIN evolves to CSCC. NF-κB-regulated DEGs show stage-specific functions: immune regulation in CIN and cancer promotion in CSCC. Short-term NF-κB activation boosts cervical cell proliferation and migration, which is reversible by an NF-κB inhibitor. Long-term NF-κB activation promotes the expression of cancer-promoting genes in normal cells and also maintains them in cancer tissues, which is linked to poorer prognosis. Inhibiting NF-κB downregulates these genes in cancer cells and suppresses the oncogenic abilities of cervical cancer cells. Collectively, NF-κB activation initiates during the simple hyperplasia stage of cervical cells, stimulating proliferation, migration, and oncogene expression. Throughout the transition from CIN to CSCC, NF-κB activation progressively intensifies, and its long-term activation promotes carcinogenesis. Thus, NF-κB is crucial in mediating cervical oncogenic transformation.

Graft-versus-host disease remains one of the most formidable barriers to the complete success of hematopoietic stem cell transplantation that has emerged as the curative approach for many hematopoietic malignancies because it affects quality of life and overall survival. Macrophages are among the important members of the immune system, which perform dual roles in GVHD as both therapeutic tools and targets. This review epitomizes the multifunctional role of macrophages in the pathophysiology of both acute and chronic GVHD. Macrophages play an important role in the early phase of GVHD because of their recruitment and infiltration into target organs. Furthermore, they polarize into two functionally different phenotypes, including M1 and M2. In the case of acute GVHD, most macrophages express the M1 phenotype characterized by the production of pro-inflammatory cytokines that contribute to tissue damage. In contrast, in chronic GVHD, macrophages tend toward the M2 phenotype associated with the repair of tissues and fibrosis. A critical balance among these phenotypes is central to the course and severity of GVHD. Further interactions of macrophages with other lymphocytes such as T cells, B cells, and fibroblast further determine the course of GVHD. Macrophage interaction associated with alloreactive T cells promotes inflammation. This is therefore important in inducing injuries of tissues during acute GVHD. Interaction of macrophages, B cell, fibroblast, and CD4+ T cells promotes fibrosis during chronic GVHD and, hence, the subsequent dysfunction of organs. These are some insights, while several challenges remain. First, the impact of the dominant cytokines in GVHD on the polarization of macrophages is incompletely characterized and sometimes controversial. Second, the development of targeted therapies able to modulate macrophage function without systemic side effects remains an area of ongoing investigation. Future directions involve the exploration of macrophage-targeted therapies, including small molecules, antibodies, and nanotechnology, which modulate macrophage behavior and improve patient outcomes. This underlines the fact that a profound understanding of the dual role of macrophages in GVHD is essential for developing new and more effective therapeutic strategies. Targeting macrophages might represent one avenue for decreasing the incidence and severity of GVHD and improving the success and safety of HSCT.

Obstructive sleep apnea (OSA) is known to contribute to the occurrence and recurrence of atrial fibrillation (AF). However, the mechanism remains unknown.

Chronic OSA rat model was established to elucidate the role of macrophages in OSA-induced AF. Moreover, to reveal the mechanisms underlying the abnormal polarization of macrophages induced by chronic OSA, co-culture cell model of macrophages and atrial myocytes was created.

Chronic OSA altered the pathological phenotype of atrial myocardial tissues, rendering it more susceptible to AF. Furthermore, chronic OSA promoted the polarization of M1 macrophages in the atrial tissue, and the AF susceptibility induced by chronic OSA was reversed upon clearance of macrophages. Then, we found that macrophages induced an atrial fibrillation-like phenotype in atrial myocytes, while atrial myocytes promoted M1 polarization of macrophages, under hypoxia/reoxygenation treatment. Moreover, hypoxia/reoxygenation upregulated the expression of hypoxia-inducible factor 1-α (HIF1α) in atrial myocytes, which subsequently promoted the expression of macrophage migration inhibitory factor (MIF) by binding to the promoter region. The increased expression of MIF further activated the expression of nuclear factor-kappa B (NF-κB) through interaction with CD74, ultimately leading to M1 macrophages polarization.

Increased polarization of M1-type macrophages was involved in the increased susceptibility to AF induced by OSA. In mechanism, OSA increased MIF expression by HIF1α in atrial myocytes. Then, MIF activated NF-κB expression by CD74 in macrophages, consequently driving the polarization of M1-type macrophages. Finally, M1 macrophages exacerbated atrial remodeling through the secretion of inflammatory cytokines, which contributed to the increased susceptibility to AF.

Ovarian cancer (OC) is one of the three most common malignant tumors of the female reproductive system, with the highest mortality rate among gynecologic malignancies. Like other tumors, OC cells undergo metabolic reprogramming phenomenon and convert glucose metabolism into "aerobic glycolysis" and generate a high concentration of lactate, i.e., the "Warburg effect", which provides a large amount of energy and corresponding intermediary metabolites for their survival, reproduction and metastasis. Numerous studies have shown that targeted inhibition of aerobic glycolysis and lactate metabolism is a promising strategy to enhance the sensitivity of cancer cells to immunotherapy. Therefore, this review summarizes the metabolic features of glycolysis in OC cells and highlights how abnormal lactate concentration affects the differentiation, metabolism, and function of infiltrating immune cells, which contributes to immunosuppression, and how targeted inhibition of this phenomenon may be a potential strategy to enhance the therapeutic efficacy of OC.

Chronic inflammation of the intestine is a significant risk factor in the development of colorectal cancer. The emergence of colitis and colorectal cancer is a complex, multifactorial process involving chronic inflammation, immune regulation, and tumor microenvironment remodeling. Macrophages represent one of the most prevalent cells in the colorectal cancer microenvironment and play a pivotal role in maintaining intestinal health and the development of colitis-associated colon cancer (CAC). Macrophages are activated mainly in two ways and resulted in three phenotypes: classically activated macrophages (M1), alternatively activated macrophages (M2). The most characteristic of these cells are the pro-inflammatory M1 and anti-inflammatory M2 types, which play different roles at different stages of the disease. During chronic inflammation progresses to cancer, the proportion of M2 macrophages gradually increases. The M2 macrophages secrete cytokines such as IL-10 and TGF-β, which promote angiogenesis and matrix remodeling, and create the favorable conditions for cancer cell proliferation, infiltration, and migration. Therefore, macrophage polarization has a dual effect on the progression of colitis to CAC. The combination of immunotherapy with reprogrammed macrophages and anti-tumor drugs may provide an effective means for enhancing the therapeutic effect. It may represent a promising avenue for developing novel treatments for CAC. In this review, we focus on the process of intestinal macrophage polarization in CAC and the role of intestinal macrophage polarization in the progression of colitis to colon cancer, and review the immunotherapy targets and relevant drugs targeting macrophages in CAC.

Tumor-associated macrophages (TAMs) significantly influence tumor progression and patient responses to conventional chemotherapy. However, the interplay between anti-cancer drugs, immune responses in the tumor microenvironment, and their implications for cancer treatment remains poorly understood. This study investigates the effects of vinorelbine on M2 macrophages in lung cancer and its capacity to modulate TAMs toward an M1 phenotype. Peripheral blood mononuclear cells (PBMCs) were polarized into M2 macrophages, and subsequent phenotype alterations upon vinorelbine treatment were assessed. Additionally, we evaluated vinorelbine's impact on gene and protein expression associated with cancer progression and cell invasion in non-small-cell lung cancer (NSCLC) cells indirectly co-cultured with M2 macrophages. Notably, vinorelbine, particularly at low concentrations, reprogrammed M2 macrophages to exhibit M1-like characteristics. While M2 macrophages enhanced cancer cell invasion, vinorelbine significantly mitigated this effect. M2 macrophages led to the overexpression of numerous genes linked to tumor growth, angiogenesis, invasion, and immune suppression in NSCLC cells, increasing the BCL2/BAX ratio and promoting cellular resistance to apoptosis. The anti-tumor efficacy of vinorelbine appears to be partly attributed to the reprogramming of M2 macrophages to the M1 phenotype, suggesting that low-dose vinorelbine may optimize therapeutic outcomes while minimizing toxicity in cancer patients.

Immune checkpoint inhibitors has opened up new avenues for cancer treatment, but serious cardiac injury has emerged in their use. A large number of data have shown that abnormal activation of cytosolic DNA-sensing cyclic GMP-AMP synthase-interferon gene activator pathway is closely related to cardiovascular inflammation and autoimmune diseases. However, the pathophysiological function of the cGAS-STING cascade in myocarditis induced by Immune checkpoint inhibitors is unclear.

In order to establish a Immune checkpoint inhibitors-associated myocarditis model, BALB/c mice were injected with mouse cardiac troponin I peptide and anti-mouse programmed death 1 antibody. Echocardiography and HE staining were then performed to assess cardiac function and inflammation. Macrophages and damaged DNA in mouse heart tissue were detected by immunofluorescence. The mitochondrial damage of macrophages was observed by electron microscope. In vitro experiments, RAW264.7 was used to detect macrophage polarization after anti-PD-1 antibody induction and STING inhibition by qPCR and flow cytometry. Mitochondrial damage was detected by immunofluorescence, and activation of the cGAS-STING signaling pathway was evaluated by protein imprinting analysis.

In the Immune checkpoint inhibitors-associated myocarditis model, DNA damage was found to activate the cGAS-STING pathway and macrophages were polarized to M1 type. In vitro experiments, anti-PD-1 antibody activate the cGAS-STING pathway through the release of damaged DNA from macrophage mitochondrial damage, causing macrophage polarization into a pro-inflammatory phenotype leading to autoimmune myocarditis.

Our results suggested that the cGAS-STING pathway played a key role in myocarditis caused by immune checkpoint inhibitors. It provided a new possibility for Immune checkpoint inhibitors to be widely used in clinic.

The tumor microenvironment is a complex environment comprising tumor cells, non-tumor cells, and other critical non-cellular components. Some studies about tumor microenvironment have recently achieved remarkable progress in tumor treatment. As a substantial part of post-translational protein modification, ubiquitination is a crucial player in maintaining protein stability in cell signaling, cell growth, and a series of cellular life activities, which are also essential for regulating tumor cells or other non-tumor cells in the tumor microenvironment. This review focuses on the role and function of ubiquitination and deubiquitination modification in the tumor microenvironment while discussing the prospect of developing inhibitors targeting ubiquity-related enzymes, thereby providing ideas for future research in cancer therapy.

The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.

This study aimed to investigate whether the polarization of monocyte-derived macrophages towards an anti-inflammatory phenotype could be hindered by modulating cellular metabolism. Several metabolic drugs were selected: Perhexiline (PerHx) and Nitazoxanide (NTZ) targeting fatty acid oxidation, CB839 (Telaglenastat) targeting glutaminolysis and Metformin (Metf) targeting the mitochondrial electron transport chain.

Our findings demonstrate that the presence of PerHx, NTZ, and CB839 during IL-4-mediated macrophages polarization impaired the acquisition of full anti-inflammatory phenotype, as evidenced by reduced expression of CD163 and CD209 and decreased secretion of CCL17 chemokine. Besides, CB839 induced tumoricidal activity in macrophages, comparable to that observed in macrophages activated by LPS and IFNγ.

This study reveals that targeting glutamine metabolism with CB839 effectively blocks the IL-4-induced anti-inflammatory phenotype in macrophages and enhances their tumor-killing capability. Our results provide a compelling rationale for repurposing metabolic drugs to create a pro-inflammatory tumor microenvironment, thereby potentially enhancing the efficacy of current immunotherapies.

FLASH radiotherapy holds promise for treating solid tumors given the potential lower toxicity in normal tissues but its therapeutic effects on tumor immunity remain largely unknown. Using a genetically engineered mouse model of medulloblastoma, we show that FLASH radiation stimulates proinflammatory polarization in tumor macrophages. Single-cell transcriptome analysis shows that FLASH proton beam radiation skews macrophages toward proinflammatory phenotypes and increases T cell infiltration. Furthermore, FLASH radiation reduces peroxisome proliferator-activated receptor-γ (PPARγ) and arginase 1 expression and inhibits immunosuppressive macrophage polarization under stimulus-inducible conditions. Mechanistically, FLASH radiation abrogates lipid oxidase expression and oxidized low-density lipid generation to reduce PPARγ activity, while standard radiation induces reactive oxygen species-dependent PPARγ activation in macrophages. Notably, FLASH radiotherapy improves infiltration and activation of chimeric antigen receptor (CAR) T cells and sensitizes medulloblastoma to GD2 CAR-T cell therapy. Thus, FLASH radiotherapy reprograms macrophage lipid metabolism to reverse tumor immunosuppression. Combination FLASH-CAR radioimmunotherapy may offer exciting opportunities for solid tumor treatment.

Elucidation of the paracrine interaction between chondrocytes and macrophages is useful for understanding the mechanisms of cartilage regeneration. Extracellular vesicles are granular substances with a diameter of approximately 150 nm, surrounded by a phospholipid bilayer membrane. In recent years, research has been conducted on clinical applications of extracellular vesicles. It has been shown that macrophages promote cartilage maturation, and macrophages acquire anti-inflammatory properties through cartilage, but the detailed mechanism of paracrine action involving extracellular vesicles remains unclear. Therefore, we focused on the effect of chondrocyte-derived extracellular vesicles on changes in macrophage characteristics.

Macrophages induced with granulocyte-macrophage colony stimulating factor (M1-like macrophages) and auricular chondrocytes were co-cultured using cell culture inserts and exosome inhibitors, and the expression of macrophage markers were analyzed. Next, extracellular vesicles separated from auricular chondrocytes were added to in vitro macrophage culture medium, and time-lapse observations of macrophage uptake of auricular chondrocyte-derived extracellular vesicles were performed. In addition, the effects of extracellular vesicles on the expression of macrophage markers were also analyzed.

The expression of CD206, an M2 macrophage marker, was increased in macrophages due to the paracrine effect of chondrocytes, and CD206 expression was further increased by pharmacological inhibition of chondrocyte-derived exosomes. It was shown that chondrocyte-derived extracellular vesicles were taken up by macrophages and promoted the production of interleukin-10, an anti-inflammatory cytokine while reducing CD206 expression.

Auricular chondrocyte-derived extracellular vesicles promoted the production of interleukin-10 in bone marrow M1-like macrophages but reduced CD206 expression.

The coagulation system is a mechanism for wound healing after injury, but it also participates in host early immune defense. The coagulation factor Ⅶ (FⅦ) can initiate extrinsic pathway and play an important role in the coagulation process. However, studies of the immune function of FVII are scarce, especially in fish. In this study, we cloned and characterized an FⅦ-like gene from large yellow croaker (Larimichthys crocea) (LcFⅦL). The open reading frame of LcFⅦL consists of 1437 base pairs and encodes 478 amino acid residues. LcFⅦL contains conserved domains that are present in other vertebrate FⅦs or FⅦLs, including a prepropeptide, a gamma-carboxy glutamic acid domain, two epidermal growth factor-like domains, and a serine protease domain. LcFⅦL was highly expressed in the liver and brain, but its expression was low in the other tested tissues. At the cellular level, LcFⅦL was highly expressed in macrophages, and its expression was induced by exposure to Pseudomonas plecoglossicida. We produced the recombinant LcFⅦL light chain (rLcFⅦL-LC), and found that it had obvious antibacterial effects against Gram-positive bacteria but low against Gram-negative bacteria. The rLcFⅦL-LC promoted the proliferation of macrophages. It also significantly induced the expression of proinflammatory factor (IL-1β and IL-6) and increased reactive oxygen species activity in large yellow croaker macrophages, while inhibited the expression of anti-inflammatory factor (TGF-β), suggesting that rLcFⅦL-LC may promote polarization of macrophages towards the M1 type. Taken together, these findings provide insight into the function of fish FⅦ, and advance our understanding of the role of the coagulation system in host defense.

Trimethylamine N-oxide (TMAO) is a gut microbial metabolite that promotes calcified aortic valve disease (CAVD), but the underlying mechanism remains obscure. Herein, we aim to test the hypothesis that TMAO regulated the inflammatory process in aortic valves via N6-methyladenosine (m6A) RNA methylation-mediated macrophage polarization.

In vitro, we stimulated macrophages (Phorbol-12-Myristate-13-Acetate-induced THP-1) with TMAO and assessed the expression of methyltransferase-like 3 (Mettl3), IL-1 receptor associated kinase M (IRAK-M) and polarization markers. The interaction between YTH domain family protein 2 (YTHDF2) and IRAK-M mRNA was explored by RNA-IP and RNA decay assay. Functionally, the effects of macrophages on human aortic valve interstitial cells (AVICs) were measured via macrophage adhesion assay and co-culture system. In vivo, the influence of IRAK-M on CAVD development was verified using Irak-m-/- mice.

Mettl3 was highly expressed while IRAK-M was decreased in human calcified aortic valves. In vitro, TMAO upregulated the expression of Mettl3, while the expression of IRAK-M, an important negative regulator of the NF-κB pathway, was remarkably decreased in macrophages. TMAO also induced classical macrophage activation (M1 polarization). Mechanistically, IRAK-M was identified as a target of Mettl3-mediated m6A modification, indicating the involvement of m6A methylation in the regulation of NF-κB activation. Moreover, RIP assay revealed the direct interaction between YTHDF2 and IRAK-M mRNA and this process was dependent on Mettl3. TMAO-treated macrophage conditioned medium induced inflammatory responses in human aortic valve interstitial cells (AVICs). In vivo experiments showed that the deletion of IRAK-M significantly accelerated the progression of aortic valve lesion in mice administrated with high-fat and choline diet (HFCD).

TMAO induces the expression of Mettl3 in macrophages. Mettl3 promotes M1 polarization of macrophages by inhibiting IRAK-M through a m6A/YTHDF2 pathway. TMAO-treated macrophages aggravate the inflammation of human AVICs.

Postoperative cognitive dysfunction (POCD) is common in the aged population and associated with poor clinical outcomes. Irisin, an endogenous molecule that mediates the beneficial effects of exercise, has shown neuroprotective potential in several models of neurological diseases. Here we show that preoperative serum level of irisin is reduced in dementia patients over the age of 70. Comprehensive proteomics analysis reveals that deletion of irisin affects the nervous and immune systems, and reduces the expression of complement proteins. Systemically administered irisin penetrates the blood-brain barrier in mice, targets the microglial integrin αVβ5 receptor, activates signal transducer and activator of transcription 6 (STAT6), induces microglia reprogramming to the M2 phenotype, and improves immune microenvironment in LPS-induced neuroinflammatory mice. Finally, prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction. Our findings provide new insights into the direct regulation of the immune microenvironment by irisin, and reveal that recombinant irisin holds great promise as a novel therapy for preventing POCD and other neuroinflammatory disorders. SUMMARY: Our findings reveal molecular and cellular mechanisms of irisin on neuroinflammation, and show that prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction.

Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as 'cell polarization.' There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations (microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke.

Spinal cord injury (SCI) represents a significant neurological disorder that profoundly impacts human life. Transplantation of extracellular vesicles (EVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) has emerged as a promising therapeutic strategy. microRNA (miRNA) containing EVs serve as crucial mediators of intercellular communication, playing vital roles in physiological and pathological processes. Research indicates that EVs from hUC-MSCs could attenuate inflammation and facilitate recovery from SCI. Nevertheless, their application in clinical treatment necessitates further investigation. We are actively pursuing an effective approach to modulate the intensity of the inflammatory response, thereby addressing secondary SCI. Initially, we activated hUC-MSCs with interleukin-4 (IL-4) and subsequently harvested their EVs. We investigated the influences of A-hUC-MSCs-EVs compared to routinely acquired EVs on macrophage polarization phenotypes both in vitro and in vivo. Our results show that EVs originating from A-hUC-MSCs are more effective at promoting macrophage polarization from the M1 phenotype to the M2 phenotype than those derived from hUC-MSCs. Notably, we found that A-hUC-MSCs-derived EVs had a superior impact on motor function recovery in mice with SCI. Importantly, we observed that IL-4 activation significantly upregulated the expression of miR-21-5p within these EVs. More specifically, our data demonstrate that A-hUC-MSCs-EVs depend on miR-21-5p to inhibit the effects of PDCD4 on macrophage polarization. This mechanism regulates inflammatory responses while simultaneously reducing apoptosis. In summary, EVs derived from IL-4 primed hUC-MSCs are enriched with miR-21-5p, which exerts a pivotal influence in shifting macrophage polarization, alleviating inflammatory responses following SCI, and facilitating recovery.