Despite the current biomaterials (e.g. titanium mesh and polyether ether ketone) have been applied to clinical skull repair, the limitations on mechanical match, shape adaptability, bioactivity and osteointegration have greatly limited their clinical application. In this work, we constructed a water and inflammatory microenvironment dual-responsive self-adaptive silk fibroin-magnesium oxide-based scaffold with the matrix metalloproteinase-2-responsive gelatin-methacryloyl-interleukin-4 (IL-4) coating, which presented good mechanical compliance, quickly shape matching and intraoperative reprocessability. With the capability of responding to an acute inflammation microenvironment followed by a triggered on-demand release of the IL-4, the combination of immunoactive IL-4 and Mg2+ co-ordinately facilitated metabolic reprogramming by suppressing glycolysis, promoting mitochondrial oxidative phosphorylation and modulating adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathways in macrophages, resulting in significantly facilitating M2 macrophage activation. During the stage of tissue remodelling, the sustained release of Mg2+ further promoted macrophage M2 polarization and the expression of anti-inflammatory cytokines, significantly reduced immune response and improved ectopic osteogenesis ability. Meanwhile, the cranial defect models of male rats demonstrated that this scaffold could significantly enhance biomineralized deposition and vascularisation, and achieve good bone regeneration of cranial defects. Overall, the bioactive scaffold provides a promising biomaterial and alternative repair strategy for critical-size skull defect repair.

Tissue engineering and regenerative medicine have emerged as crucial disciplines focused on the development of new tissues and organs to overcome the limitations of traditional treatments for tissue damage caused by accidents, diseases, or aging. Strontium ion (Sr2+) has garnered significant attention for its multifaceted role in promoting regeneration medicine and therapy, especially in bone tissue regeneration. Recently, numerous studies further confirm that Sr2+ also plays a critical in soft tissue regeneration. This review firstly summarizes the influence of Sr2+ on critical biological processes such as osteogenesis, angiogenesis, immune modulation, matrix synthesis, mineralization, and antioxidative defence mechanisms. Then details the classification, properties, advantages, and limitations of Sr-containing biomaterials (SrBMs). Additionally, this review extends to the current applications of SrBMs in regenerative medicine for diverse tissues, including bone, cartilage, skeletal muscle, dental pulp, cardiac tissue, skin, hair follicles, etc. Moreover, the review addresses the challenges associated with current SrBMs and provides insights for their future designing and applications in regenerative medicine.

The peripheral nervous system is a complex ecological network, and its injury triggers a series of fine-grained intercellular regulations that play a crucial role in the repair process. The peripheral nervous system is a sophisticated ecological network, and its injury initiates a cascade of intricate intercellular regulatory processes that are instrumental in the repair process. Despite the advent of sophisticated microsurgical techniques, the repair of peripheral nerve injuries frequently proves inadequate, resulting in adverse effects on patients' quality of life. Accordingly, the continued pursuit of more efficacious treatments is of paramount importance. In this paper, a review of the relevant literature from recent years was conducted to identify the key cell types involved after peripheral nerve injury. These included Schwann cells, macrophages, neutrophils, endothelial cells, and fibroblasts. The review was conducted in depth. This paper analyses the phenotypic changes of these cells after injury, the relevant factors affecting these changes, and how they coordinate with neurons and other cell types. In addition, it explores the potential mechanisms that mediate the behaviour of these cells. Understanding the interactions between these cells and their mutual regulation with neurons is of great significance for the discovery of new neuroregenerative treatments and the identification of potential therapeutic targets.

Early coagulation-inflammation interaction and late in-stent restenosis undermine the efficacy of vascular stents after implantation. Targeting the interplay between inflammation and coagulation, and smooth muscle cell (SMC) proliferation, we presented a microenvironment-responsive coating designed to regulate tissue responses and vascular regeneration throughout the remodeling process. Coagulation was inhibited by incorporating anticoagulant tirofiban into the coating. MMP9-responsive nanoparticles embedded in the coating released salvianolic acid A to modulate inflammatory cell behavior and inhibit SMC dysfunction. By effectively interfering with clotting and inflammation, the coating suppressed platelet-fibrin interaction and formation of platelet-monocyte aggregates, thereby mitigating adverse effects on reendothelialization. Its ability to influence SMC proliferation and migration resulted in reduced intimal hyperplasia. Coated stents were shown to significantly regulate tissue regeneration, improve the vascular environment and even reduced the lipid content in the narrowed atherosclerotic vessels in vivo. This direct approach enhanced the vascular tissue regeneration after stent implantation, and offered promising insights for optimizing vascular stent design.

The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges after an ischemic stroke, which promotes neuronal death and inhibits nerve tissue regeneration. As the first immune cells to be activated after an ischemic stroke, microglia play an important immunomodulatory role in the progression of the condition. After an ischemic stroke, peripheral blood immune cells (mainly T cells) are recruited to the central nervous system by chemokines secreted by immune cells in the brain, where they interact with central nervous system cells (mainly microglia) to trigger a secondary neuroimmune response. This review summarizes the interactions between T cells and microglia in the immune-inflammatory processes of ischemic stroke. We found that, during ischemic stroke, T cells and microglia demonstrate a more pronounced synergistic effect. Th1, Th17, and M1 microglia can co-secrete pro-inflammatory factors, such as interferon-γ, tumor necrosis factor-α, and interleukin-1β, to promote neuroinflammation and exacerbate brain injury. Th2, Treg, and M2 microglia jointly secrete anti-inflammatory factors, such as interleukin-4, interleukin-10, and transforming growth factor-β, to inhibit the progression of neuroinflammation, as well as growth factors such as brain-derived neurotrophic factor to promote nerve regeneration and repair brain injury. Immune interactions between microglia and T cells influence the direction of the subsequent neuroinflammation, which in turn determines the prognosis of ischemic stroke patients. Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke. However, such studies have been relatively infrequent, and clinical experience is still insufficient. In summary, in ischemic stroke, T cell subsets and activated microglia act synergistically to regulate inflammatory progression, mainly by secreting inflammatory factors. In the future, a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells, along with the activation of M2-type microglia. These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.

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.

Papillary thyroid carcinoma (PTC), comprising 85% of all thyroid cancers, is an epithelial malignancy. The potential for malignant transformation in normal cells by thyroid cancer cells via exosomal Annexin A1 (ANXA1) delivery is investigated in this study. Our aim is to determine the impact of PTC cells on macrophage polarization through exosomal ANXA1 secretion and its implications for tumor progression. Exosomes in PTC cells were examined using transmission electron microscopy, exosome labeling, and nanoparticle tracking analysis. Real-time quantitative polymerase chain reaction was employed to quantify gene expression levels. Protein levels were determined through Western blot analysis. The interplay between genes was assessed using luciferase reporter and RNA pull-down assays. Functional experiments were conducted to investigate PTC cell proliferation and apoptosis. Our findings reveal that ANXA1 promotes PTC cell proliferation and inhibits apoptosis. Exosomes derived from PTC cells were found to promote macrophage M2 polarization. ANXA1 stimulates M2 polarization through the activation of the PI3K/AKT pathway. MicroRNA-374a-5p (miR-374a-5p) and microRNA-374b-5p (miR-374b-5p) were identified as inhibitors of ANXA1 expression and PI3K/AKT pathway activity, thereby inhibiting macrophage M2 polarization. Furthermore, miR-374a-5p and miR-374b-5p were observed to suppress PTC cell proliferation through their regulatory action on ANXA1. Our study suggests that miR-374a/b-5p inhibits PTC cell growth by blocking the macrophage M2 polarization induced by exosomal ANXA1.

Macrophages can maintain gut immune homeostasis by driving clearance of infection, but also can prevent chronic inflammation and induce tissue repair. Reduced nicotinamide adenine dinucleotide (NAD+) levels in macrophages have been reported to be associated with the onset of severe colitis. Given that dysregulation of gut macrophages plays a significant role in inflammatory bowel disease (IBD), they represent a potential target for novel therapies. Here we show an IBD therapeutic candidate LMT503, a substrate that modulates NADH quinone oxidoreductase (NQO1), which induces anti-inflammatory macrophage polarization by NAD+ enhancement. To determine the anti-inflammatory effect of LMT503, a dextran sulfate sodium (DSS)-induced colitis mouse model was used in this study. Treatment of bone marrow-derived macrophages (BMDMs) with LMT503 increased IL-10 and Arg1 levels but decreased levels of TNF-α, iNOS, and IL-6. LMT503 also increased levels of SIRT1, SIRT3, and SIRT6, suggesting that macrophages were driven to an anti-inflammatory character. In a murine DSS-induced colitis model, oral treatment with LMT503 ameliorated colonic inflammation and decreased infiltrating monocytes and neutrophils. Although NAD+ enhancement did not alter CX3CR1intCD206- or CX3CR1hiCD206+ colon macrophage population, it decreased levels of TNF-α and iNOS and increased IL-10 level, with colonic macrophages showing an anti-inflammatory character shift. Depletion of CX3CR1 expressing gut resident macrophages abrogated the immune regulatory effect of LMT503 in the colon. These data suggest that LMT503 is a therapeutic candidate that can target macrophages to drive polarization with an immunosuppressive character and ameliorate IBD.

Cardiac fibrosis poses a significant challenge in cardiovascular diseases due to its intricate pathogenesis, and there is currently no standardized and effective treatment approach. The fibrotic process entails the involvement of various cell types and molecular mechanisms, such as fibroblast activation and proliferation, increased collagen synthesis, and extracellular matrix rearrangement. Traditional therapies often fall short in efficacy or carry substantial side effects. However, recent studies have shown that Chimeric Antigen Receptor T (CAR-T) cells can selectively target and eliminate activated cardiac fibroblasts (CFs) in mice, leading to reduced cardiac fibrosis and improved myocardial tissue compliance. This breakthrough presents a new and promising avenue for treating cardiac fibrosis. Currently, CAR-T cell-based therapy for cardiac fibrosis is undergoing animal experimentation, indicating ample scope for enhancement. Future investigations could explore the application of CAR cell therapy in cardiac fibrosis treatment, including the potential of CAR-natural killer (CAR-NK) cells and CAR macrophages (CAR-M), offering novel insights and strategies for combating cardiac fibrosis.

Patients with osteosarcoma (OS) exhibit metastasis upon diagnosis, and the condition frequently acquires resistance to traditional chemotherapy treatments, failing the therapy. The objective of this research was to examine the impact of curculigoside (Cur), a key phenolic compound discovered in the rhizome of C. orchioides Gaertn, on OS cells and the surrounding tumor environment.

We assessed the impact of curculigoside on tumor inhibition in four osteosarcoma cell lines and mice tumor xenograft models using various techniques including cell viability assay, wound healing assay, cell apoptosis analysis, immunofluorescent staining, and IHC. Moreover, we created a mini-PDX model by utilizing freshly obtained primary OS cells from surgically removed OS tissues to evaluate the possible clinical use of Cur.

The results of our study show that Cur triggers cell death in OS cells and enhances the maturation of RAW264.7 cells. By effectively inhibiting the growth of OS cells, these actions mechanistically trigger the catastrophic buildup of unbound iron and uncontrolled lipid peroxidation, ultimately resulting in ferroptosis. Moreover, additional validation of Cur's substantial antineoplastic impact is obtained through in vivo experiments employing xenograft and mini-PDX models.

To sum up, this research is the initial one to exhibit the anti-tumor effects of Cur on OS using various methods, indicating that Cur shows potential as a viable approach for treating OS.

Mathematical models describing the growth of plaque in the arteries (e.g., Friedman and Hao (2015), Friedman et al. (2015), Hao and Friedman (2014), McKay et al. (2005) and Mukherjee et al. (2019)) were introduced. All of these models include the interaction of the "bad" cholesterols, low-density lipoprotein (LDL), and the "good" cholesterols, high-density lipoprotein (HDL), in triggering whether plaque will grow or shrink. Because the blood vessels tend to be circular, 2D cross-section model is a good approximation, and the 2D models are studied in Friedman et al. (2015), Zhang et al. (2023) and Zhao and Hu (2022). A bifurcation into a 3D plaque was recently studied in Huang and Hu (2022). All of these models assume a constant supply of LDL and HDL from the blood vessel. In reality, nutrient concentration changes with the intake of food, which happens very often in a periodic manner. When the LDL and HDL supplies from the blood vessel are periodic and are not too far away from the prevalent values, a periodic solution was obtained in Huang and Hu (2023). In this paper, we carry out the linear stability analysis of this periodic solution and provide simulation results to confirm our analysis.

Polysaccharides from various cyanobacterial species have attracted attention for their potential health benefits. In this study, polysaccharide extracts from a freshwater Nostoc sp. were explored for their potential in immunomodulation relevant to skincare, and particularly wound care. Nostoc sp. polysaccharides (NSPs) were tested in various cellular and molecular assays using RAW264.7 macrophages and skin cell lines (HDF, HaCaT). Polysaccharides from the Nostoc sp. outer layer (OL) and inner fluid (IF) significantly enhanced cell proliferation and migration of HDF. HaCaT scratch-wound healing improved with certain polysaccharide extracts. Inner fluid fractions IF-2B and IF-3B polysaccharides demonstrated anti-inflammatory effects in RAW264.7 cells, while IF-1B reduced TNF-α and IL-8 expression in HaCaT cells. TNF-α, though not promoting cell proliferation, positively impacted phagocytosis and NO production. NSPs exhibited weak anticoagulation properties, and fraction IF-1B with monomer composition (Ara/3.0: Glc/23.7: Man/20.3: GlcA/28.0) accelerated wound healing; importantly, OL-1B along with all of the IF cold and hot-extracted fractions were non-cytotoxic, suggesting significant potential for developing skin therapeutics, including pharmaceutical and cosmetic products, based on active compounds from Nostoc sp.. The study underscores the underexplored potential of Nostoc sp. extracts in skincare and highlights the potential benefits of these bioactive components for therapeutic applications.

Injectable biomaterials, such as thermosensitive chitosan (CH)-based hydrogels, present a highly translational potential in dentistry due to their minimally invasive application, adaptability to irregular defects/shapes, and ability to carry therapeutic drugs. This work explores the incorporation of azithromycin (AZI) into thermosensitive CH hydrogels for use as an intracanal medication in regenerative endodontic procedures (REPs). The morphological and chemical characteristics of the hydrogel were assessed by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and Fourier transform infrared spectroscopy (FTIR). The thermosensitivity, gelation kinetics, compressive strength, cytocompatibility, and antibacterial efficacy were evaluated according to well-established protocols. An in vivo model of periapical disease and evoked bleeding in rats' immature permanent teeth was performed to determine disinfection, tissue repair, and root formation. AZI was successfully incorporated into interconnected porous CH hydrogels, which retained their thermosensitivity. The mechanical and rheological findings indicated that adding AZI did not adversely affect the hydrogels' strength and injectability. Incorporating 3 % and 5 % AZI into the hydrogels led to minimal cytotoxic effects compared to higher concentrations while enhancing the antibacterial response against endodontic bacteria. AZI-laden hydrogel significantly decreased E. faecalis biofilm compared to the controls. Regarding tissue response, the 3 % AZI-laden hydrogel improved mineralized tissue formation and vascularization compared to untreated teeth and those treated with double antibiotic paste. Our findings demonstrate that adding 3 % AZI into CH hydrogels ablates infection and supports neotissue formation in vivo when applied to a clinically relevant model of regenerative endodontics.

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.

Cerebral arteriovenous malformation is a congenital blood vessel abnormality with its immune mechanism remains unclear. Our study characterized the change of cellular composition and gene expression landscape in brain arteriovenous malformation (bAVM).

We conducted single-cell RNA sequencing analysis on one bAVM sample and three healthy control (HC) samples. Cell clustering analysis and cell type annotation were used to identify the major cell types in bAVM and HC samples. Critical differentially expressed genes between bAVM and HC sample were analyzed in each cell types to explore the functional changes of each kind of cells. We also examined the cell communication change in bAVM sample and identified the significantly changed cellular interaction pathways.

5 major cell types were identified including NK cells, monocytes, fibroblasts, endothelial cells (EC), tissue stem cells and smooth muscle cells (SMC). In bAVM sample, proportion of monocytes raised significantly while SMC decreased. Inflammation and cell migration related genes expression and cell communication pathways changed dramatically in bAVM sample.

Inhibition of monocyte-endothelium interaction and promotion of NK cells interaction were found in bAVM sample, which may reveal a new mechanism about inflammation response and cellular impairment in the disease progression.

Tumor-associated macrophages (TAMs) are pivotal components of the breast cancer (BC) tumor microenvironment (TME), significantly influencing tumor progression and response to therapy. However, the heterogeneity and specific roles of TAM subpopulations in BC remain inadequately understood.

We performed an integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) data from BC patients to comprehensively characterize TAM heterogeneity. Utilizing the MetaTiME computational framework and consensus clustering, we identified distinct TAM subtypes and assessed their associations with clinical outcomes and treatment responses. A machine learning-based predictive model was developed to evaluate the prognostic significance of TAM-related gene expression profiles.

Our analysis revealed three distinct TAM subgroups. Notably, we identified a novel macrophage subtype, M_Macrophage-SPP1-C1Q, characterized by high expression of SPP1 and C1QA, representing an intermediate differentiation state with unique proliferative and oncogenic properties. High infiltration of M_Macrophage-SPP1-C1Q was significantly associated with poor overall survival (OS) and chemotherapy resistance in BC patients. We developed a Random Forest (RF)-based predictive model, Macro.RF, which accurately stratified patients based on survival outcomes and chemotherapy responses, independent of established prognostic parameters.

This study uncovers a previously unrecognized TAM subtype that drives poor prognosis in BC. The identification of M_Macrophage-SPP1-C1Q enhances our understanding of TAM heterogeneity within the TME and offers a novel prognostic biomarker. The Macro.RF model provides a robust tool for predicting clinical outcomes and guiding personalized treatment strategies in BC patients.

Klebsiella pneumoniae (KP) infections represent a significant global health challenge, characterized by severe inflammatory sequelae and escalating antimicrobial resistance. This comprehensive review elucidates the complex interplay between macrophages and KP, encompassing pathogen recognition mechanisms, macrophage activation states, cellular death pathways, and emerging immunotherapeutic strategies. We critically analyze current literature on macrophage pattern recognition receptor engagement with KP-associated molecular patterns. The review examines the spectrum of macrophage responses to KP infection, including classical M1 polarization and the newly described M(Kp) phenotype, alongside metabolic reprogramming events such as glycolytic enhancement and immune responsive gene 1 (IRG1)-itaconate upregulation. We systematically evaluate macrophage fate decisions in response to KP, including autophagy, apoptosis, pyroptosis, and necroptosis. Furthermore, we provide a critical assessment of potential future therapeutic modalities. Given the limitations of current treatment paradigms, elucidating macrophage-KP interactions is imperative. Insights gained from this analysis may inform the development of novel immunomodulatory approaches to augment conventional antimicrobial therapies, potentially transforming the clinical management of KP infections.

Mesenchymal stem cells (MSCs) play a crucial role in regenerative medicine due to their regenerative potential. However, traditional MSC-based therapies are hindered by issues such as microvascular obstruction and low cell survival after transplantation. Exosomes derived from MSCs (MSC-Exo) provide a cell-free, nanoscale alternative, mitigating these risks and offering therapeutic potential for liver diseases. Nonetheless, the functional variability of MSCs from different sources complicates their clinical application. Stem cells derived from human exfoliated deciduous teeth (SHED) offer advantages such as ease of procurement and robust proliferative capacity, but their secretome, particularly SHED-Exo, remains underexplored in the context of liver disease therapy. This study analyzed MSC-Exo from various sources via small RNA sequencing to identify differences in microRNA profiles, aiding in the selection of optimal MSC sources for clinical use. SHED-Exo was subsequently tested in an acute liver injury model, showing notable regenerative effects, including enhanced hepatocyte proliferation, macrophage polarization, and reduced inflammation. Despite strong liver-targeting properties, the rapid hepatic clearance of SHED-Exo limits its effectiveness in chronic liver diseases. To address this challenge, a GelMA-based hydrogel was developed for in situ delivery, ensuring sustained release and enhanced antifibrotic efficacy, providing a promising strategy for chronic liver disease management.

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.

As aging progresses, the structures and functions of immune organs such as the thymus and spleen deteriorate, leading to impaired immune function and immune senescence. This study investigated the potential of umbilical cord mesenchymal stem cells (UC-MSCs) to mitigate D-galactose-induced immune senescence by enhancing the structural and functional integrity of aging immune organs and regulating the gut microbiota. The findings show that UC-MSCs treatment significantly delayed thymus and spleen atrophy and reduced the number of senescence-associated β-galactosidase (SA-β-gal) positive cells. At the molecular level, UC-MSCs treatment downregulated the expression of aging-related genes, including p16, p53, p21, and RB. It also boosted antioxidant enzyme activity, increasing the levels of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), while decreasing serum malondialdehyde (MDA) levels by activating the Nrf2/HO-1 pathway. Additionally, UC-MSCs treatment restored the balance of the gut microbiota. These results demonstrate that UC-MSCs significantly improve the structural and functional integrity of immune organs and enhance the composition of the gut microbiome, offering a potential strategy for delaying immune senescence.

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.

Background: Head and neck cancer (HNC) evades immune responses by manipulating the tumor immune microenvironment (TIME). Tumor-bound Axl has been implicated in promoting an immunosuppressive TIME in HNC, though its precise role remains unclear. Understanding Axl's contribution to immune evasion in HNC could lead to the identification of new therapeutic targets; therapies directed at these targets could be combined with and thereby enhance immunotherapies. Results: Using Axl knockout (Axl KO) cell lines derived from the immunologically "cold" MOC2 mouse model, we found that Axl loss delayed tumor growth in immunocompetent mice. This was accompanied by reduced immunosuppressive cells, including MDSCs, Tregs, B cells, and neutrophils, and increased infiltration of cytotoxic CD8 T cells and NK cells. To identify the immune population(s) responsible for these changes, Axl KO tumors were implanted in immune-deficient mice. Axl KO tumor growth in athymic nude mice (which lack T cells) was unchanged, whereas tumor growth in NCG mice (which lack NK cells) was rescued, suggesting that NK cells mediate the Axl KO tumor growth delay. Further, Axl loss enhanced NK cell cytotoxicity in vitro and in vivo, and NK cell depletion reversed delayed Axl KO tumor growth. Mechanistically, Axl KO tumors showed decreased expression of CD73 and CCL2, which inhibit NK cells, and increased expression of CCL5 and CXCL10, which promote NK cell recruitment and activation. Conclusions: These novel findings suggest that tumor-bound Axl fosters an immunosuppressive TIME by inhibiting NK cell recruitment and function, thereby promoting tumor growth. Targeting Axl may enhance NK cell-mediated tumor killing and improve immunotherapy efficacy in HNC.

Renal fibrosis is a critical pathological characteristic of chronic kidney disease, and current antifibrotic therapies has limited efficacy. Sodium butyrate (NaB) has been shown to be highly effective in mitigating bleomycin-induced pulmonary fibrosis; however, its specific impact on renal fibrosis and the underlying mechanisms remain unclear. This study aims to elucidate the role and mechanism of NaB in renal fibrosis by using a mouse model of renal fibrosis induced through Unilateral Ureteral Obstruction (UUO) and folic acid (FA) administration.

NaB significantly decreased the distribution of collagen fibers in renal tissues and mitigated fibrosis in a dose-dependent manner. Further analysis indicated that NaB inhibited M2 macrophage polarization in the renal tissues of UUO model mice by blocking the phosphorylation of STAT6, hence reducing renal fibrosis. Additionally, in vitro experiments demonstrated that NaB inhibited fibroblast activation induced by M2 macrophages. Mechanistic studies revealed that NaB attenuates fibroblast activation and M2 macrophage polarization by upregulating LKB1 and inhibiting the activation of the STAT6 signaling pathway.

NaB may exert its effects by inhibiting the activation of the IL-4/STAT6 signaling pathway through the upregulation of LKB1, which suppress the polarization of M2 macrophages and consequently reduce renal fibrosis. These findings establish a theoretical foundation for NaB as a novel drug candidate for renal fibrosis and indicate its potential applicability in clinical treatments for this condition.

The pathogenesis of atopic dermatitis (AD) is closely linked to both genetic and environmental factors, with patients often exhibiting a range of immunological abnormalities, including a pronounced Th2-type overreaction, which is a key feature of the disease.

Cutibacterium acnes has been shown to induce a robust Th1 immune response through intraperitoneal injections, potentially preventing the development of AD. In this study, a novel nanoparticulate formulation of Cutibacterium acnes (NFCA) was developed with the formulation optimization for the dermal delivery.

Sponge Haliclona sp. spicules (SHS) were isolated from the explants of sponge Haliclona sp. with our proprietary method. The NFCA was prepared by high-speed grinding followed by film extrusion. The skin penetration of the model drugs in NFCA with SHS were visualized using confocal microscopy. The therapeutic effects of NFCA coupled with SHSs against AD in mice were assessed by using pathohistological examination and cytokine ELISA assay.

The NFCA particle size was 254.1±39.4 nm, with a PDI of 0.29±0.08 and a Zeta potential of -7.9±0.6 mV. SHS significantly enhanced total skin absorption of FD10K (39.6±6.7%, p=0.00076) as well as deposition in the viable epidermis (3.2±1.6%, p=0.08) and deep skin (dermis & receptor) (36.0±5.9%, p=1.82E-5) compared to the control. In vitro cytotoxicity tests showed that NFCA had low toxicity to HaCaT cells (IC50=63.8 mg/mL). The study confirmed that NFCA can activate immune signaling pathways, promoting the high expression of IL-6 and IL-8 in keratinocytes, enhancing TNF-α and IL-1β expression in macrophages, and inducing Th1 and Th17-type immune responses. Furthermore, we demonstrated that the dermal delivery of NFCA using SHS in vivo significantly reduced epidermal thickness, serum IgE levels, and tissue IL-4 levels, thereby accelerating skin repair and mitigating Th2 polarization.

SHS were employed to effectively deliver NFCA to the deeper skin layers to exert its immune functions. Moreover, the combination of SHS and NFCA can significantly cure mice with atopic dermatitis.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an emerging zoonotic pathogen with different pathogenesis in humans and camels. The mechanisms behind the higher tolerance of camels to MERS-CoV infection are still unknown. Monocytes are innate myeloid cells that are able, depending on the local stimulation in their microenvironment, to differentiate into different functional subtypes of macrophages with an impact on the adaptive immune response. Several in vitro protocols have been used to induce the differentiation of monocyte-derived macrophages (MDMs) in human and several veterinary species. Such protocols are not available for camel species. In the present study, monocytes were separated from camel blood and differentiated in vitro in the presence of different stimuli into MDM. Camel MDMs generated in the presence of a combined stimulation of monocytes with LPS and GM-CSF resulted in the development of an M1 macrophages phenotype with increased abundance of the antigen-presentation receptor MHCII molecules and a decreased expression of the scavenger receptor CD163. The expression pattern of the cell markers CD163, CD14, CD172a, CD44, and CD9 on MDM generated in the presence of the MERS-CoV S1 protein revealed similarity with M-CSF-induced MDM, suggesting the potential of the MERS-CoV S1 protein to induce an M2 macrophages phenotype. Similarly to the effect of M-CSF, MERS-CoV-S protein-induced MDMs showed enhanced phagocytosis activity compared to non-polarized or LPS/GM-CSF-polarized MDMs. Collectively, our study represents the first report on the in vitro generation of monocyte-derived macrophages (MDMs) in camels and the characterization of some phenotypic and functional properties of camel MDM under the effect of M1 and M2 polarizing stimuli. In addition, the results suggest a polarizing effect of the MERS-CoV S1 protein on camel MDMs, developing an M2-like phenotype with enhanced phagocytosis activity. To understand the clinical relevance of these in vitro findings on disease pathogenesis and camel immune response toward MERS-CoV infection, further studies are required.

Cichorium intybus is a traditional medicinal herb for hepatitis treatment in China and Europe. Sesquiterpene lactones are the main active ingredients in C. intybus. However, their structure-activity relationship (SAR) and molecular mechanisms of anti-inflammatory and hepatoprotective effects require further elucidation.

To identify new sesquiterpene lactones from C. intybus, and further evaluate their anti-inflammatory effects, SAR, and mechanisms of anti-inflammatory and hepatoprotective properties.

Identification of sesquiterpene lactones from C. intybus using chromatographic fractionation, NMR, and mass spectrometry. The repression of inflammation was evaluated in RAW264.7 macrophages incubated with LPS. Western blotting was employed to investigate the anti-inflammatory mechanisms. The hepatoprotective effect was measured in LPS/D-galactosamine (D-GalN)-induced acute hepatitis in mice.

We identified 3 new sesquiterpene lactones and 15 known analogues from C. intybus. SAR analysis showed that the α-methylene-γ-lactone moiety was essential for their anti-inflammatory properties. Furthermore, 8-deoxylactucin was identified as the most potent anti-inflammatory component in LPS-induced RAW264.7 macrophages by reduction of nitric oxide production via inhibiting iNOS expression, and suppression of IL-1β, IL-6, and TNF-α expression. Mechanistically, 8-deoxylactucin not only blocked LPS-induced IKKα/β phosphorylation, IκBα phosphorylation and degradation, and NF-κB nuclear accumulation, but also enhanced NRF2 expression and nuclear translocation, HO-1 and NQO1 expression, and reduced ROS generation in vitro. In vivo, 8-deoxylactucin mitigated LPS/D-GalN-induced acute hepatitis, which manifested as reduction in inflammatory infiltration, live injury, serum levels of AST and ALT, and production of pro-inflammatory cytokines and 4-hydroxynonenal.

8-Deoxylactucin, the sesquiterpene lactone isolated from C. intybus, exerted anti-inflammatory and hepatoprotective effects by blocking NF-κB activation and enhancing NRF2 activation.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons, leading to escalating muscle weakness, atrophy, and eventually paralysis. While neurons are the most visibly affected, emerging data highlight microglia-the brain's resident immune cells-as key contributors to disease onset and progression. Rather than existing in a simple beneficial or harmful duality, microglia can adopt multiple functional states shaped by internal and external factors, including those in ALS. Collectively, these disease-specific forms are called disease-associated microglia (DAM). Research using rodent models, patient-derived cells, and human postmortem tissue shows that microglia can transition into DAM phenotypes, driving inflammation and neuronal injury. However, these cells can also fulfill protective roles under certain conditions, revealing their adaptable nature. This review explores recent discoveries regarding the multifaceted behavior of microglia in ALS, highlights important findings that link these immune cells to motor neuron deterioration, and discusses emerging therapies-some already used in clinical trials-that aim to recalibrate microglial functions and potentially slow disease progression.

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.

Catalpol (CAT) is a landmark active ingredient in traditional Chinese medicine Rehmannia (TCT), also known as dehydroxybenzoate catalpone, which is a kind of iridoid terpene glycoside with strong antioxidant, anti-inflammatory, antitumor and other biological activities. It can exert its anti-disease effect in a variety of ways. For some patients with chronic diseases, the application of azalea alcohol in rehmannia may bring more comprehensive and long-lasting efficacy. Studies have shown that the anti-disease effect of catalpol in osteoporosis (OP) is mainly achieved through various pathways such as Wnt/β-catenin signaling pathways to promote osteogenic differentiation, and RANKL/RANK and other signaling pathways to inhibit osteoclastic differentiation. At present, there is a slight lack of analysis of the mechanism of action of catalpa alcohol in the treatment of osteoporosis, so this study comprehensively searched the literature on the mechanism of action of catalpa alcohol in the treatment of osteoporosis in various databases, and reviewed the research progress of its role and mechanism, to provide reference and theoretical basis for the further development and application of catalpol.

Angiostrongylus cantonensis (AC) is the leading cause of eosinophilic meningoencephalitis worldwide. The neuroimmune interactions between peripheral and central immune systems in angiostrongyliasis remain unclear. In this study, significant infiltration of eosinophils, myeloid cells, macrophages, neutrophils, and Ly6C monocytes is observed in the brains of AC-infected mice, with macrophages being the most abundant. RNA-seq and SMART-seq analysis of pattern recognition receptor (PRR) and DNA sensor gene sets revealed a marked increase in Z-DNA binding protein 1 (Zbp1) expression in infected mice. Confocal microscopy, RT-qPCR, western blotting, and immunohistochemistry further confirmed that Zbp1 is specifically upregulated in macrophages and microglia. Using Zbp1-knockout mice and flow cytometry, it is found that knockout of Zbp1 enhanced lymphocyte infiltration and natural killer cell cytotoxicity, modulating the immune microenvironment in the central nervous system (CNS) during AC infection. Mechanistically, it is revealed that in macrophage Zbp1 directly binds to receptor-interacting protein 3 (RIP3) to promote its phosphorylation, subsequently facilitating the phosphorylation of mixed lineage kinase domain-like protein (Mlkl). The activated Zbp1-pRIP3-pMlkl axis leads to necroptosis and upregulates pro-inflammatory cytokines including TNF-α, IL-1α, CXCL9, CXCL10 in macrophages, which recruits and activates immune cells. These findings offer new insights into the pathogenic mechanisms of angiostrongyliasis and suggest potential therapeutic strategies.

As the global population ages, an increasing number of elderly people are experiencing weakened bone regenerative capabilities, resulting in slower bone repair processes and associated risks of various complications. This review outlines the research progress on biomaterials that promote bone repair through immunotherapy. This review examines how manufacturing technologies such as 3D printing, electrospinning, and microfluidic technology contribute to enhancing the therapeutic effects of these biomaterials. Following this, it provides detailed introductions to various anti-osteoporosis drug delivery systems, such as injectable hydrogels, nanoparticles, and engineered exosomes, as well as bone tissue engineering materials and coatings used in immunomodulation. Moreover, it critically analyzes the current limitations of biomaterial-mediated bone immunotherapy and explores future research directions for material-mediated bone immunotherapy. This review aims to inspire new approaches and broaden perspectives in addressing the challenges of bone repair and aging by exploring innovative biomaterial-mediated immunotherapy strategies.

Cancer stem cells (CSCs) are considered key drivers of progression in head and neck squamous cell carcinoma (HNSCC). Our single-cell RNA sequencing (scRNA-seq) analysis revealed predominant expression of CD271 in CSCs, however, its role as a CSC marker in HNSCC requires further elucidation. We investigated the stemness characteristics of CD271high HNSCC cells and their interactions with the tumor immune microenvironment.

scRNA-seq data from hypopharyngeal squamous cell carcinoma (HPSCC) tissues were analyzed to identify expression profile of CSCs. Overall survival was compared between CD271high and CD271low patients based on immunostaining of HPSCC samples. The stemness of CD271high HNSCC cells was evaluated via an in vivo limiting dilution assay. In a C57BL/6 mice model, the percentage of immune cells and macrophage subtypes were analyzed by flow cytometry. The role of CD271 in macrophage polarization was further examined by in vitro coculture of CD271high cells with CD14+ monocytes. Gene expressions were analyzed by qPCR.

CD271 is predominantly expressed in CSCs identified by scRNA-seq analysis. CD271 enhances HNSCC cell proliferation and is negatively correlated with patient prognosis in HPSCC. CD271 knockdown suppressed HNSCC tumor growth and regulated macrophage polarization within the TME. CD271high cells exhibited stemness features and enhanced tumor growth in vivo.

CD271high HNSCC cells exhibit CSC characteristics and regulate macrophage polarization. Targeting CD271 may improve the immunosuppressive TME to inhibit tumor growth. Combining CD271-targeting agents with other therapies presents a promising strategy that may enhance therapeutic efficacy and prognosis in HNSCC.

Recently, the importance of peri-implant soft tissue integration quality has been recognised as an essential factor in the long-term success of dental implant rehabilitation.

The aim of this study was to explore the influence of three materials commonly used in implant dentistry, namely titanium (Ti), dental adhesive resin (Re) and polyetheretherketone (PEEK), on the peri-implant soft tissues.

In this clinical randomised comparative study, 37 bone-level implants were placed, and experimental transmucosal healing abutments made of different materials were randomly assigned to each implant. These abutments were removed together with the surrounding soft tissues after 8 weeks. Immunohistochemical analyses were performed to determine the presence and localisation of different immune cells. In addition, clinical and radiographic data were collected and peri-implant bone remodeling was assessed.

Compared to the Ti and PEEK groups, Re abutments revealed a higher infiltration of macrophages in the connective tissue (p = 0.04) and neutrophils in the adjacent epithelium (p = 0.03). In the Re abutments, peri-implant bone remodeling was higher compared to the other groups (p = 0.01).

The use of resin material as a transmucosal healing abutment should be carefully considered as it was associated with a higher presence of inflammatory cells at 8 weeks post-implantation as well as superior bone remodeling compared to PEEK and Ti.

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.

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.

Breast cancer is one of the most common cancers worldwide, 30-50 % of patients with advanced breast cancer develop brain metastasis, causing severe damage to their life quality. Due to the existence of the blood-brain barrier (BBB), brain lesions were recognized to be a unique microenvironment with limited infiltration of circulating immune cells and drugs. However, emerging studies reported the immunology of the brain tumor microenvironment (TME) and indicated the potential of immunotherapy against brain metastases. Therefore, it is of great value to comprehensively investigate the TME and identify the pro-tumoral mechanisms facilitating brain metastases and the crucial molecules involved in this process. In this research, we re-analyzed public data on three brain surgical specimens of breast cancer metastases and identified the immunosuppressive roles of macrophages in the metastatic TME. Then, we conducted the first single-cell RNA sequencing on a murine model of breast cancer brain metastasis. In the brain TME, immune cells showed prominent heterogeneity, especially the mononuclear phagocyte system (MPS). We identified the alteration of macrophage subclusters in the central nerve system (CNS) after breast cancer invasion and found that metastatic cancer cells re-shaped the TME cellular interactions for immune evasion and nutrition supply. Finally, this research could serve as a reference for further analysis of new therapies against brain metastatic lesions.

Biomaterial composition and surface charge play a critical role in macrophage polarization, providing a molecular cue for immunomodulation and tissue regeneration. In this study, we developed bifunctional hydrogel inks for accelerating M2 macrophage polarization and exosome (Exo) cultivation for wound healing applications. For this, we first fabricated polyamine-modified three-dimensional (3D) printable hydrogels consisting of alginate/gelatin/polydopamine nanospheres (AG/NSPs) to boost M2-exosome (M2-Exo) secretion. The cultivated M2-Exo were finally encapsulated into a biocompatible collagen/decellularized extracellular matrix (COL@d-ECM) bioink for studying angiogenesis and in vivo wound healing study. Our findings show that 3D-printed AGP hydrogel promoted M2 macrophage polarization by Janus kinase/signal transducer of activation (JAK/STAT), peroxisome proliferator-activated receptor (PPAR) signaling pathways and facilitated the M2-Exo secretion. Moreover, the COL@d-ECM/M2-Exo was found to be biocompatible with skin cells. Transcriptomic (RNA-Seq) and real-time PCR (qRT-PCR) study revealed that co-culture of fibroblast/keratinocyte/stem cells/endothelial cells in a 3D bioprinted COL@d-ECM/M2-Exo hydrogel upregulated the skin-associated signature biomarkers through various regulatory pathways during epidermis remodeling and downregulated the mitogen-activated protein kinase (MAPK) signaling pathway after 7 days. In a subcutaneous wound model, the 3D bioprinted COL@d-ECM/M2-Exo hydrogel displayed robust wound remodeling and hair follicle (HF) induction while reducing canonical pro-inflammatory activation after 14 days, presenting a viable therapeutic strategy for skin-related disorders.

Our previous study revealed that mesenchymal stem cells (MSCs) can secrete large amounts of the chemokine CCL2 under inflammatory conditions and alleviate idiopathic pneumonia syndrome (IPS) by promoting regulatory CCR2 + CD4 + T-cell formation through the CCL2‒CCR2 axis. Given the abundance of macrophages in lung tissue, how these macrophages are regulated by MSC-based prophylaxis via IPS and their interactions with T cells in lung tissue during allo-HSCT are still not fully understood.

An IPS mouse model was established, and MSC-based prophylaxis was administered. In vitro coculture systems and an IPS model were used to study the interactions among MSCs, macrophages and T cells.

Prophylactic administration of MSCs induced M2 polarization and alleviated acute graft-versus-host disease (aGVHD) and lung injury in an IPS mouse model. In vitro coculture studies revealed that M2 polarization was induced by MSC-released CCL2 and that these M2 macrophages promoted the formation of regulatory CCR2 + CD4 + T cells. Blocking the CCL2-CCR2 interaction in vitro reversed MSC-induced M2 polarization and abolished the induction of CCR2 + CD4 + T-cell formation. Additionally, in vivo administration of a CCL2 or CCR2 antagonist in the IPS mouse model exacerbated aGVHD and lung injury, accompanied by a reduction in M2 macrophages and reduced formation of regulatory CCR2 + CD4 + T cells in lung tissue.

MSCs alleviate IPS by facilitating M2 polarization via the CCL2‒CCR2 axis and further inducing the formation of regulatory CCR2 + CD4 + T cells.