Stem cell therapy has revolutionized the management of osteoarthritis (OA), but the articular dysregulated redox status diminishes cell engraftment efficiency and disrupts immune homeostasis, therefore compromising the overall therapeutic efficacy. Here, we present hydrogen (H2) generators-backpacked mesenchymal stem cells (MSCs) which preserve the biological functions and survival of transplanted cells and reverse articular immune dysfunction, mitigating OA. Specifically, post systemic transplantation, H2 generators-laden MSCs home to OA joints, and upon stimulation in acidic OA environment, H2 produced from the generators remodels articular redox balance, thereby relieving the loss of mitochondrial membrane potential, decreasing cell apoptosis rate, and maintaining pluripotent and paracrine functions of MSCs. Furthermore, the reactive oxygen species scavenging by H2 in combination with paracrine effects of the MSCs promote macrophage polarization towards the anti-inflammatory M2 phenotype, which contributes to reversing synovial immune disorder. In severe OA model, the backpacked MSCs reduce osteoarthritic degeneration, osteophyte formation and joint inflammation, and promote cartilage regeneration. In sum, our work demonstrates that arming with H2 generators effectively boosts the therapeutic efficacy of MSCs, which hold great potential for alleviating redox imbalance-related tissue lesions, including but not limited to OA.

Myocardial ischemia-reperfusion injury (MIRI) has become a severe threat to human health due to its high mortality rate and poor prognosis. Mutually entangled issues including ROS over-production, excessive inflammatory responses, and myocardial apoptosis are involved during MIRI. Effective inhibition of ROS burst at the beginning of reperfusion has been proved as the key for MIRI treatment. In this work, we report a superoxide anion-responsive peptide co-assembly (S/A-P) capable of delivering the H2S donor (i.e., superoxide-responsive persulfide donor) and all-trans retinoic acid (ATRA) simultaneously for the treatment. Our results suggest that compared with its single peptidic counterparts, the as-prepared system can significantly lower ROS production and repair myocardial mitochondrial dysfunction due to the synergy effect from the persulfides/H2S and ATRA. Moreover, S/A-P can reduce excessive inflammatory response through regulating macrophage polarization, which is further mapped by RNA sequencing. In vivo assessment of the co-assembly also displays an excellent therapeutic effect of MIRI on rats. In terms of good biocompatibility and outstanding efficacy, we believe that S/A-P will have a bright future for the treatment of cardiovascular diseases or other related diseases.

Xanthine oxidoreductase (XOR) inhibitors are used to treat gout, inhibiting uric acid production, which causes clinical symptoms. Commonly used XOR inhibitors are the small molecule febuxostat (Fbx) and the purine analogue allopurinol (Allo). Recent studies show that XOR inhibitors can reduce mature interleukin (IL)-1β production by activated macrophages. This effect is not due to reduced uric acid crystal formation, which can induce NLRP3 inflammasome activation, but an independent effect. Fbx and Allo have been used interchangeably in in vitro studies to highlight the role of XOR in pro-inflammatory macrophage function. Here, we analysed the effects of Fbx and Allo on pro-inflammatory macrophage signatures. Both XOR inhibitors maintain pro-inflammatory macrophage metabolic and phenotypic hallmarks. However, only Fbx reduces the activity of caspase-1 and the release of IL-1β by preventing inflammasome assembly in macrophages isolated from both mice and humans. Our study identified an Fbx-specific reduction in IL-1β production, which could be used clinically to reduce the deleterious effects of macrophage-derived IL-1β.

Ideal periodontal regeneration requires the integration of alveolar bone, periodontal ligament, and cementum, along with Sharpey's fibers for occlusal force resistance. However, physiological regeneration remains rare due to its intricate structure, making clinical regeneration a challenge. Periodontal ligament stem cells (PDLSCs), first isolated in 2004, hold the key to multi-directional differentiation into cementoblasts, fibroblasts, and osteoblasts. While traditional therapies like guided tissue regeneration (GTR) aim to activate PDLSCs, clinical outcomes are inconsistent, suggesting the need for additional strategies to enhance PDLSCs' functions. Advancements in molecular biotechnology have introduced the use of recombinant growth factors for tissue regeneration. However, maintaining their efficacy requires high doses, posing cost and safety issues. Multi-layered scaffolds combined with cell sheet technology offer new insights, but face production, ethical, and survival challenges. Immune regulation plays a crucial role in PDLSC-mediated regeneration. The concept of "coagulo-immunomodulation" has emerged, emphasizing the coupling of blood coagulation and immune responses for periodontal regeneration. Despite its potential, the clinical translation of immune-based strategies remains elusive. The "developmental engineering" approach, which mimics developmental events using embryonic-stage cells and microenvironments, shows promise. Our research group has made initial strides, indicating its potential as a viable solution for periodontal complex regeneration. However, further clinical trials and considerations are needed for successful clinical application. This review aims to summarize the strategic transitions in the development of periodontal regenerative materials and to propose prospective avenues for future development.

In this research work, we report the development of a new immunoengineering approach of sustained drug delivery for regenerative medicine applications. We have produced an innovative nanobiomaterial that integrates the unique advantages of zein, as a protein-based delivery system, with maresin-1, a specialised pro-resolving mediator that plays a critical role in controlling inflammation and promoting its resolution. A microfluidic chip was used as a manufacturing platform to load maresin-1 into zein nanoparticles, by flow-focusing the organic central stream with the aqueous outer fluid. We were able to develop homogeneous nanoparticles presenting a mean diameter between 100 and 117 nm. Different drug loadings were tested: 10, 50, and 100 nM of maresin-1. The nanoparticles loaded with the highest concentration of maresin-1 presented a more controlled release profile throughout 72 h. The biocompatibility and immunomodulatory potential were assessed in primary human macrophages. Maresin-1-loaded zein nanoparticles were non-cytotoxic and, the nanoparticles loaded with 100 nM maresin-1 significantly enhanced macrophage polarisation towards an anti-inflammatory M2-like phenotype, as evidenced by a pronounced increase in the M2/M1 ratio. This polarisation effect was higher than that obtained with free maresin-1 or empty zein nanoparticles, highlighting the synergistic potential of this nanocarrier system. This work emphasizes maresin-1-loaded zein nanoparticles as a safe and effective immunomodulatory platform, paving the way for novel therapeutic approaches in inflammation management and tissue repair and regeneration.

Gastric cancer (GC) is a malignant tumor with one of the highest morbidity and death rates in the world. Neoadjuvant therapy, including neoadjuvant chemotherapy (NAC) and NAC combined with immunotherapy, can improve the resection and long-term survival rates. However, not all patients respond well to neoadjuvant therapy. It has been confirmed that immune cells in the tumor immune microenvironment, including T cells, B cells, and natural killer cells, can affect the efficacy of neoadjuvant therapy. This paper summarizes current preclinical and clinical evidence to more fully describe the effects of neoadjuvant therapy on the immune microenvironment of GC, to provide the impetus to identify biomarkers to predict the potency of neoadjuvant therapy, and to identify the mechanisms of drug resistance, which should promote the development of individualized and accurate treatments for GC patients.

Liver fibrosis is a wound-healing response induced by persistent liver damage, resulting from complex multicellular interactions and multifactorial networks. Without intervention, it can progress to cirrhosis and even liver cancer. Current understanding suggests that liver fibrosis is reversible, making it crucial to explore effective therapeutic strategies for its alleviation. Chronic inflammation serves as the primary driver of liver fibrosis, with hepatic macrophages playing a dual role depending on their polarization state. This review summarizes various prevention and therapeutic strategies targeting hepatic macrophages in the context of liver fibrosis. These strategies include inhibition of macrophage recruitment, modulation of macrophage activation and polarization, regulation of macrophage metabolism, and induction of phagocytosis and autophagy in hepatic macrophages. Additionally, we discuss the communication between hepatic macrophages, hepatocytes, and hepatic stellate cells (HSCs), as well as the current clinical application of anti-fibrotic drugs targeting macrophages. The goal is to identify effective therapeutic targets at each stage of macrophage participation in liver fibrosis development, with the aim of using hepatic macrophages as a target for liver fibrosis treatment.

As the global population ages, age-related bone defects have become a major public health challenge. The decline in bone tissue repair capacity among the elderly is primarily attributed to the senescence of bone marrow mesenchymal stem cells (BMSCs), which leads to reduced proliferation and differentiation capabilities, thereby impeding the bone healing process. Additionally, the deterioration of the bone microenvironment, characterized by chronic inflammation and oxidative stress, further complicates bone repair. To address these issues, a multifunctional hydrogel drug delivery system, the metformin-loaded carboxymethyl chitosan/tannic acid/manganese (MCTM) hydrogel was developed. This system integrates the synergistic effects of CMCS, TA, Mn2+, and metformin to effectively alleviate BMSCs senescence, optimize the local chronic inflammatory microenvironment, eliminate oxidative stress, and reduce post-implantation infection risks. Detailed material characterization revealed that the introduction of Mn2+ significantly enhances the mechanical properties and optimizes the degradation characteristics of the CMCS/TA hydrogel, ensuring continuous and stable drug release at tissue repair sites. In vitro and in vivo experiments demonstrated MCTM's excellent biocompatibility and its ability to combine stem cell senescence alleviation with bone repair microenvironment improvement, thereby effectively overcoming various adverse factors affecting bone defect repair in the elderly. This study presents a promising strategy for enhancing bone regeneration under senescent conditions.

Macrophages represent a crucial cell type within the immune system, exhibiting significant adaptability that allows for the transformation into various phenotypes in response to their surrounding environment. This review investigates the characteristics of various macrophage phenotypes and their functional roles in disease pathogenesis and resolution. The M1 phenotype, recognized for its inflammatory attributes, plays a pivotal role in combating infections and tumors; however, it may also contribute to tissue injury, persistent inflammation, and the pathogenesis of autoimmune and inflammatory diseases. Conversely, the M2 phenotype is associated with anti-inflammatory activities and tissue repair processes. But this is not the end of the story and researches illustrated novel phenotypes that may provide new approaches and therapeutic opportunities. Recent progress in characterizing distinct macrophage phenotypes has enabled the development of innovative therapeutic strategies for chronic inflammatory conditions, autoimmune disorders, and cancers. This review underscores the critical role of macrophage polarization, illustrating how various stimuli can influence macrophage fate and modify their responses. Additionally, it explores the implications of macrophage plasticity on disease progression and treatment efficacy. A comprehensive understanding of these dynamics is essential for the advancement of targeted immunotherapies, which possess the potential to transform treatment strategies for a variety of medical conditions.

Superficial surgical site infection (SSI) is a significant risk factor for the development of periprosthetic joint infection (PJI), particularly in diabetic patients. A high-glucose microenvironment is observed to compromise phagocytosis by inducing cellular senescence, which leads to impaired antibacterial immune function. Exosomes derived from umbilical cord stem cells (H-Exos) can reverse the immunosuppressive microenvironment by rejuvenating senescent cells, thereby terminating excessive, persistent, and ineffective inflammatory responses. Thus, a novel exosome-based immunotherapeutic antibacterial strategy to reverse fate is proposed. Vancomycin & lysostaphin-loaded exosomes are incorporated in a customizable microneedle patch (ExoV-ExoL@MN) for controlled release, enabling tailored treatments for diverse clinical scenarios. While rejuvenating macrophage senescent phenotype, the antibiotics encapsulated within exosomes can be responsively released by the hemolysin secreted by bacteria, triggering rapid bacterial killing. Post-infection clearance, they induce a shift from M1 to M2 macrophage polarization, thereby enhancing anti-inflammatory and reparative responses. Furthermore, the components can be mixed on demand and at any time, allowing for real-time customization and fabrication directly at the clinic (fabrication@clinic). This strategy reverses the immunosuppressive microenvironment by rejuvenating senescent macrophages and effectively combats bacterial invasion into deep tissues through bacteria-responsive antibiotic release, providing a promising approach for preventing and treating SSI-induced PJI.

Autoimmune diseases are a class of chronic disorders characterized by the aberrant activation of the immune system, where macrophages play a central role in regulating immune responses during disease onset and progression. Ferroptosis, a form of iron-dependent programmed cell death, has recently attracted significant interest due to its involvement in various pathological conditions. In macrophages, ferroptosis not only compromises cell viability but also disrupts immune homeostasis by promoting pro-inflammatory responses and suppressing anti-inflammatory pathways, thereby intensifying inflammation and exacerbating disease severity. While substantial progress has been made in elucidating macrophage ferroptosis in atherosclerosis and oncology, its precise mechanistic role in autoimmune diseases remains largely unexplored. This review systematically summarizes the molecular mechanisms of macrophage ferroptosis and its regulatory effects on immune homeostasis, with particular emphasis on its role in autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), and systemic sclerosis (SSc). Furthermore, we discuss potential therapeutic targets related to macrophage ferroptosis in these conditions. By integrating current knowledge, this review aims to provide a theoretical framework and novel perspectives for developing innovative therapeutic strategies targeting autoimmune diseases.

Macrophages are the first line of defense in the innate immune system. Macrophages have two subtypes: classically activated macrophages (M1) and alternatively activated macrophages (M2), with different phenotypes and functions. They play a critical role in defending against pathogens and maintaining internal homeostasis. Macrophages have great plasticity in their biological characteristics. Although the regulation of macrophage plasticity has not been fully elucidated, accumulated evidence supports that microenvironmental differences are the root cause for macrophage differentiation into different subtypes. These differences alter macrophage plasticity by modulating key metabolites, activating downstream gene transcription, and influencing phagocytosis, cytokine secretion, and immune regulation. Herein, we systematically summarize metabolic reprogramming, including glucose, lipid, amino acid, ion, vitamin, nucleotide, and butyrate metabolism, as key regulators affecting macrophage polarization, providing new insights for developing targeted drugs that modulate macrophage plasticity.

Macrophages are crucial immune cells in periodontal tissues, which play key roles in both the destruction and repair of associated with periodontitis. Targeted modulation of macrophage function has emerged as a potentially effective approach to influence periodontitis progression. This study investigates the effects of methotrexate-loaded extracellular vesicles (MTX-EVs) on inflammatory macrophage polarization both in vivo and in vitro. In a murine periodontitis model, MTX-EVs inhibited alveolar bone resorption, suppressed pro-inflammatory macrophage activation, and promoted anti-inflammatory macrophages. Mechanistically, MTX-EVs reduced acyl-CoA synthetase-1 (ACSL1) expression, which was elevated during inflammation. Inhibition of ACSL1 with triacsin-C in macrophages suppressed the inflammatory phenotype through the promotion of the oxidative phosphorylation (OXPHOS). In contrast, MTX-EVs counteracted the effects of ACSL1 overexpression on macrophage polarization and metabolism. Our findings suggest that targeting ACSL1 via MTX-EVs represents a therapeutic strategy for modulating macrophage polarization and improving periodontitis treatment outcomes.

Sjogren's syndrome (SS) is an autoimmune disease involving macrophage infiltration of the exocrine glands. LTK, a receptor tyrosine kinase, is involved in many autoimmune diseases, such as lupus erythematosus. The objectives of this study was to explore the impact of LTK on autophagy in SS.

The NCBI Gene Expression Omnibus (GEO) database was used to screen for differentially expressed genes (DEGs) in SS patients and validated by quantitative reverse transcription PCR (RT-qPCR) in A253 cells with EGF and IFN-γ. Meanwhile, lentiviral vectors were used to transfect A253 cells for stable LTK silencing. CCK-8, flow cytometry, and transmission electron microscopy (TEM), Western blotting (WB) was employed to assess proliferation, apoptosis, autophagy, and autoimmune antigens (Ro52/SSA and La/SSB) in A253 cells. Then, macrophages were treated with 100 ng/ml of LPS to induce the polarization of macrophages towards the M1 phenotype, while macrophages were treated with IL-4 to activate the macrophage M2 phenotype. LTK-silenced A253 cells were co-cultured with macrophages. WB as well as flow cytometry were used to assess macrophage polarization markers. Furthermore, protein-antibody microarrays were utilized to analyze downstream proteins regulated by LTK. Finally, the functionality of LTK was confirmed in NOD/ShiLtJ mice.

LTK expression in the GEO database was increased in SS patients. And LTK was also significantly increased by EGF and IFN-γ. Knockdown of LTK increased proliferation and autophagy in A253 cells. While LTK deficiency inhibited the expression of Ro52/SSA and La/SSB, and apoptosis in A253 cells. Furthermore, LTK-silenced A253 cells promoted polarization of macrophages towards the M2 phenotype, which is associated with the pathogenesis of SS. Knockdown of LTK resulted in reduced expression of CXCL13, which in turn triggered macrophage M2 polarization. Additionally, LTK deficiency ameliorated submandibular gland tissue damage and inhibited autoimmune antigens secretion in NOD/ShiLtJ mice. In addition, the expression of autophagy markers and M2 polarization markers in the submandibular gland tissue was increased by shLTK.

LTK could promote progressive SS pathogenesis via CXCL13. This discovery indicates that targeting LTK/CXCL13 could be a potential therapeutic strategy for the clinical management of SS.

Cardiac adaptation to hypoxic injury is regulated by dynamic interactions between cardiomyocytes and macrophages, yet the impacts of immune phenotypes on cardiac structure and contractility remain poorly understood. To address this, we developed the immuno-heart on a chip, a novel in vitro platform to investigate cardiomyocyte-macrophage interactions under normoxic and hypoxic conditions. By integrating neonatal rat ventricular myocytes (NRVMs) and bone marrow-derived macrophages-polarized to pro-inflammatory (M1) or pro-healing (M2/M2*) phenotypes-we elucidated the dual protective and detrimental roles macrophages play in modulating cardiomyocyte cytoskeletal architecture and contractility. Pro-inflammatory stimulation reduced cardiomyocyte structural metrics (z-line length, fraction, and integrity) in normoxic co-cultures. Under hypoxia, M1-stimulated NRVM monocultures exhibited declines in cytoskeletal organization-quantified by actin and z-line orientational order parameters. Relative to monocultures, M1-stimulated co-cultures attenuated hypoxia-induced active stress declines but produced weaker normoxic stresses. In contrast, pro-healing stimulation improved normoxic z-line metrics and preserved post-hypoxia cytoskeletal organization but reduced normoxic contractility. Notably, M2-stimulated macrophages restored normoxic contractility and preserved post-hypoxia systolic stress, albeit with increased diastolic stress. RNAseq analysis of M2-stimulated co-cultures identified upregulated structural and immune pathways driving these hypoxia-induced changes. Cytokine profiles revealed stimulation-specific and density-dependent tumor necrosis factor-alpha and interleukin-10 secretion patterns. Together, these findings quantitatively link clinically relevant macrophage phenotypes and cytokines to distinct changes in cardiac structure and contractility, offering mechanistic insights into immune modulation of hypoxia-induced dysfunction. Moreover, the immuno-heart on a chip represents an innovative framework to guide the development of future therapies that integrate immune and cardiac targets to enhance patient outcomes.

Wound infections are one of the major threats to human health, accounting for millions of deaths annually. Real-time monitoring, accurate diagnosis, and on-demand therapy are crucial to minimizing complications and saving lives. Herein, we propose a "monitor-and-treat" strategy for infected wound management by integrating the emerging development of bacterio-therapeutics and bio-optics. The upper layer consists of gelatin methacryloyl (GelMA)-collagen III methacryloyl (Col3MA) (GC), Reuterin (Reu) isolated from the probiotic Lactobacillus reuteri (L. reuteri) and microfluidic safflower polysaccharide (SPS)@GelMA microspheres using 3D printing technology. The lower layer is made of acryloylated glycine (ACG) hydrogel with tissue adhesion capability, which enables the hydrogel to adapt to the movement and stretching of the skin. By integrating temperature-sensitive polydimethylsiloxane (PDMS) optical fibers, the ACG-GC/Reu/SPS-PDMS hydrogel could accurately and steadily sense and send wound temperature information to intelligent devices for real-time monitoring of the healing status ("monitor"). The double-layered hydrogel not only inhibited bacterial survival and colonization (97.4 % against E. coli and 99 % against S. aureus), but also exhibited remarkable hemostatic properties. Furthermore, it was conducive to L929 cell proliferation and pro-angiogenesis, and promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype, therefore creating a favorable immune microenvironment at the wound site. Animal experiments using SD rats and Bama minipigs demonstrated that this hydrogel promoted wound closure, directed polarization to M2 macrophages, alleviated inflammation, enhanced neovascularization, therefore accelerating infected wound healing ("treat"). In addition, RNA-Seq analysis revealed the mechanism of action of ACG-GC/Reu/SPS-PDMS hydrogel in modulating key signaling pathways, including down-regulation of AMPK, IL-17, and NF-κB signaling pathways, activation of NLRP3 inflammatory vesicles, and enrichment of MAPK, TGF-β, PI3K-Akt, TNF, and VEGF signaling pathways. The modulation of these signaling pathways suggests that hydrogels play an important role in the molecular mechanisms that promote wound healing and tissue regeneration. Therefore, the design of this study provides an innovative and multifunctional bandage strategy that can significantly improve pathologic diagnosis and wound treatment.

Liver metastasis can occur in a wide range of cancers and have a significant impact on patient survival and prognosis. Once liver metastasis occurs, patients often lose the opportunity for surgery, and although a small percentage of patients can undergo hepatic resection to prolong survival, the benefit is not great. There were also many factors affecting liver metastasis, including reprogramming of the primary tumor metabolism, disturbances in the immune microenvironment and immune cells, alterations in the gut microbiota, and epigenetic changes. Interleukin-10 (IL-10) has a dual role as a cytokine that has been found in recent years to be pro-inflammatory as well as pro-liver metastasis. IL-10 exerts pro-metastatic effects mainly by regulating the polarization of tumor macrophages in the tumor microenvironment, especially by promoting the polarization of M2 macrophages. However, the role of IL-10 in tumorigenesis and progression remains controversial and the molecular mechanism involved in promoting liver metastasis is currently unclear. In view of the increasing role of IL-10 in promoting liver metastasis, this review summarizes the role of IL-10 in liver metastasis of colorectal cancer, breast cancer and other tumors in recent years, and provides ideas for subsequent clinical practice and basic research.

A growing number of studies have shown that in addition to adaptive immune cells such as CD8 + T cells and CD4 + T cells, various other cellular components within prostate cancer (PCa) tumor microenvironment (TME), mainly tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs), have been increasingly recognized as important modulators of tumor progression and promising therapeutic targets.

In this review, we aim to delineate the mechanisms by which TAMs, CAFs and MDSCs interact with PCa cells in the TME, summarize the therapeutic advancements targeting these cells and discuss potential new therapeutic avenues.

We searched PubMed for relevant studies published through December 10 2023 on TAMs, CAFs and MDSCs in PCa.

TAMs, CAFs and MDSCs play a critical role in the tumorigenesis, progression, and metastasis of PCa. Moreover, they substantially mediate therapeutic resistance against conventional treatments including anti-androgen therapy, chemotherapy, and immunotherapy. Therapeutic interventions targeting these cellular components have demonstrated promising effects in preclinical models and several clinical trials for PCa, when administrated alone, or combined with other anti-cancer therapies. However, the lack of reliable biomarkers for patient selection and incomplete understanding of the mechanisms underlying the interactions between these cellular components and PCa cells hinder their clinical translation and utility.

New therapeutic strategies targeting TAMs, CAFs, and MDSCs in PCa hold promising prospects. Future research endeavors should focus on a more comprehensive exploration of the specific mechanisms by which these cells contribute to PCa, aiming to identify additional drug targets and conduct more clinical trials to validate the safety and efficacy of these treatment strategies.

Cancer cachexia, a multifactorial syndrome characterized by body weight loss, muscle, and adipose tissue wasting, affects patients with cancer. Over time, the definition of cachexia has been modified, including inflammation as one of the main causal factors. Evidence has suggested that a range of proinflammatory mediators may be involved in the regulation of intracellular signaling, resulting in enhanced resting energy expenditure, metabolic changes, and muscle atrophy, all of which are typical features of cachexia. Physiologically speaking, however, inflammation is a response aimed at facing potentially damaging events. Along this line, its induction in the cancer hosts could be an attempt to restore the physiological homeostasis. Interesting observations have shown that cytokines such as interleukins 4 and 6 could improve muscle wasting, supporting the view that the same mediator may exert pro- or anti-inflammatory activity depending on the immune cells involved as well as on the tissue metabolic demand. In conclusion, whether inflammation is crucial to the occurrence of cachexia or just one contributor among others, is still unclear. Indeed, while inflammation is a trigger of cachexia, the alterations of energy and protein metabolism and of the hormonal homeostasis occurring in cachexia likely act as inflammatory stimuli on their own. Whether the causative role prevails over the compensatory one likely depends on the tumor type and stage, patient lifestyle, the presence of comorbidities, and the response to anticancer treatments paving the way to a holistic, personalized approach to cancer cachexia.

Inflammatory bowel disease (IBD) is a chronic inflammatory bowel disease with unclear causes and limited treatment options. Sodium butyrate (NaB), a byproduct of dietary fiber in the intestine, has demonstrated efficacy in treating inflammation. However, the precise anti-inflammatory mechanisms of NaB in colon inflammation remain largely unexplored. This study aims to investigate the effects of NaB on dextran sulfate sodium (DSS)-induced colitis in rats. The findings indicate that oral administration of NaB effectively prevent colitis and reduce levels of serum or colon inflammatory factors. Additionally, NaB demonstrated in vitro inhibition of RAW264.7 inflammation cytokines induced by LPS, along with suppression of the ERK and NF-κB signaling pathway activation. Moreover, NaB mitigated LPS and Nigericin-induced RAW264.7 pyroptosis by reducing indicators of mitochondrial damage, including increased mitochondrial membrane potential (JC-1) levels and decreased Mito-ROS production. NaB increases ZO-1 and Occludin expression in CaCo2 cells by inhibiting RAW264.7 pyroptosis. These results suggest that NaB could be utilized as a therapeutic agent or dietary supplement to alleviate colitis.

Acute liver injury (ALI) is a prevalent inflammatory disease with no currently available effective targeted therapies that characterized by high mortality and morbidity. Dihydroartemisinin (DHA), a derivative of the renowned antimalarial compound artemisinin, has garnered attention for its anti-inflammatory property. However, the precise anti-inflammatory mechanisms underlying its efficacy in treating ALI remain unclear. Notably, the excessive inflammatory cytokines secreted by macrophages represents a critical factor of liver damage. In our comprehensive study, transcriptome and proteomic analysis of M1 macrophages after DHA treatment was performed to unearth the potential anti-inflammatory targets for ALI treatment. Transcriptomics analysis indicated that DHA significantly mitigated inflammation, primarily by downregulating the expressions of CCL1, CCL2, CCL7, CCL13, and CXCL13. Concurrently, proteomics analysis identified six proteins, such as CYBA and CYBB, that were consistently downregulated in the DHA intervention groups compared to the M1 group. Intriguingly, a protein-protein interaction network analysis highlighted the close association of CYBA and CYBB with the aforementioned chemokine genes. Through meticulous screening, DHA curtailed the production of reactive oxygen species (ROS) by targeting CYBA and CYBB, subsequently suppressing the secretion of several chemokines and dampening the inflammatory response in M1 macrophages. More importantly, DHA not only reduced ROS and chemokine levels but also restored liver function by downregulating CYBA and CYBB to inhibit NF-κB pathway in ALI mice, demonstrating strong anti-inflammatory effects. In conclusion, our findings throw novel light into the underlying anti-inflammatory mechanism of DHA in ALI management, offering valuable insights for future clinical research and therapeutic strategies for inflammatory diseases.

Disruption of local microbial irritation and host immune response can result in inflammation and tissue destruction in periodontitis. Studies on the modulation of macrophage polarization could help attenuate immune responses in periodontal tissues. To investigate the effect of ubiquitin-specific protease-7 (USP7) and its inhibitor P5091 on the polarization of macrophages in periodontitis, gene expression in periodontitis tissues and normal control were analyzed via single-cell RNA sequencing data and mice model experimental periodontitis. RAW264.7 cells were induced to M1 polarization with LPS + IFN-γ and M2 polarization with IL-4. USP7 was knocked down using lentivirus, and the effect of USP7 inhibitor P5091 on macrophage polarization was comparatively analyzed. The expression of Usp7 and polarization markers were detected by qRT-PCR. Western blot was used to examine the polarization markers and pathway-associated proteins. Results indicated that USP7 expression was elevated in tissues affected by periodontitis. Periodontitis macrophages and M1 polarized macrophages had higher USP7 expression. Knockdown of USP7 revealed an inhibition of both M1 and M2 macrophage polarization. Inhibition of USP7 with P5091 resulted in the decreased expression of M1 polarization markers and phosphorylation of P65, but the increased expression of M2 polarization markers and phosphorylation of STAT6. In conclusion, USP7 is involved in regulating macrophage polarization in periodontitis and its inhibitor P5091 may contribute to the prevention of periodontitis.

With the gradual understanding of glioma development and the immune microenvironment, many immune cells have been discovered. Despite the growing comprehension of immune cell functions and the clinical application of immunotherapy, the precise roles and characteristics of immune cell subtypes, how glioma induces subtype transformation of immune cells and its impact on glioma progression have yet to be understood.

In this review, we comprehensively center on the four major immune cells within the glioma microenvironment, particularly neutrophils, macrophages, lymphocytes, myeloid-derived suppressor cells (MDSCs), and other significant immune cells. We discuss (1) immune cell subtype markers, (2) glioma-induced immune cell subtype transformation, (3) the mechanisms of each subtype influencing chemotherapy resistance, (4) therapies targeting immune cells, and (5) immune cell-associated single-cell sequencing. Eventually, we identified the characteristics of immune cell subtypes in glioma, comprehensively summarized the exact mechanism of glioma-induced immune cell subtype transformation, and concluded the progress of single-cell sequencing in exploring immune cell subtypes in glioma.

In conclusion, we have analyzed the mechanism of chemotherapy resistance detailly, and have discovered prospective immunotherapy targets, excavating the potential of novel immunotherapies approach that synergistically combines radiotherapy, chemotherapy, and surgery, thereby paving the way for improved immunotherapeutic strategies against glioma and enhanced patient outcomes.

Post-mastectomy radiotherapy plays a crucial role in breast cancer treatment but can lead to an inflammatory response causing soft tissue damage, particularly radiation-induced capsular contracture (RICC), impacting breast reconstruction outcomes. Adipose-derived stem cells (ADSCs), known for their regenerative potential via paracrine capacity, exhibit inherent radiotolerance. The influence of tumor necrosis factor-alpha (TNF-α) on ADSCs has been reported to enhance the paracrine effect of ADSCs, promoting wound healing by modulating inflammatory responses.

This study investigates the potential of TNF-α-treated human ADSCs (T-hASCs) on silicone implants to alleviate RICC, hypothesizing to enhance suppressive effects on RICC by modulating inflammatory responses in a radiation-exposed environment.

In vitro, T-hASCs were cultured on various surfaces to assess viability after exposure to radiation up to 20 Gy. In vivo, T-hASC and non-TNF-α-treated hASC (C-hASCs)-coated membranes were implanted in mice before radiation exposure, and an evaluation of the RICC mitigation took place 4 and 8 weeks after implantation. In addition, the growth factors released from T-hASCs were assessed.

In vitro, hASCs displayed significant radiotolerance, maintaining consistent viability after exposure to 10 Gy. TNF-α treatment further enhanced radiation tolerance, as evidenced by significantly higher viability than C-hASCs at 20 Gy. In vivo, T-hASC-coated implants effectively suppressed RICC, reducing capsule thickness. T-hASCs exhibited remarkable modulation of the inflammatory response, suppressing M1 macrophage polarization while enhancing M2 polarization. The elevated secretion of vascular endothelial growth factor from T-hASCs is believed to induce macrophage polarization, potentially reducing RICC.

This study establishes T-hASCs as a promising strategy for ameliorating the adverse effects experienced by breast reconstruction patients after mastectomy and radiation therapy. The observed radiotolerance, anti-fibrotic effects, and immune modulation suggest the possibility of enhancing patient outcomes and quality of life. Further research and clinical trials are warranted for broader clinical uses.

This study investigates the therapeutic effects of D-Xylose, a natural sugar, on non-alcoholic fatty liver disease (NAFLD), focusing on the expression of the lysozyme gene (LYZ) in macrophages. Using the single-cell dataset GSE136103 for NAFLD, researchers analyzed macrophage populations and other groups utilizing the Seurat package in R, while a differential analysis was performed on the NAFLD dataset GSE61260 using the limma package. Both in vitro and in vivo models, including cell culture, mouse models, RT-qPCR, Western blot, ELISA, and histopathological analyses, were employed to examine the effect of D-Xylose on lipid accumulation, LYZ expression, blood lipid levels, and inflammatory responses. The study found a significant upregulation of LYZ in free fatty acid (FFA)-treated cells and mouse liver tissues, with a subsequent reduction after D-Xylose intervention. Treatment with D-Xylose and Amlodipine led to a notable decrease in lipid accumulation, as evidenced by reduced triglyceride and cholesterol levels. D-Xylose demonstrated a greater improvement in lipid metabolism than Amlodipine. Additionally, D-Xylose significantly mitigated inflammatory responses, reducing levels of inflammatory markers such as IL1R, IL6, MYS8, TNF, NF-κB, and IL-1. Furthermore, D-Xylose administration significantly reduced liver weight and liver index, with a positive impact on serum liver function and blood lipid levels. The findings suggest that D-Xylose could be a therapeutic intervention for NAFLD by targeting LYZ expression in macrophages, thereby modulating lipid metabolism and inflammatory responses.

Critical-size bone defects remain a significant clinical challenge. The lack of endogenous stem cells with osteogenic differentiation potential in the defect area, combined with the inflammatory responses induced by scaffold implantation, highlights the need for biomaterials that can deliver stem cells and possess inflammatory regulation properties. In this study, we developed a 3D bioprinted gelatin methacrylate (GelMA) hydrogel scaffold modified with luteolin-loaded ZIF-8 (LUT@ZIF-8) nanoparticles, designed to deliver bone marrow mesenchymal stem cells (BMSCs) to the defect site and release bioactive components that promote osteogenesis and modulate the immune microenvironment. The LUT@ZIF-8/GelMA hydrogel scaffolds demonstrated excellent physical properties and biocompatibility. The sustained release of luteolin and zinc ions from the LUT@ZIF-8 nanoparticles conferred antibacterial, osteoinductive, and inflammatory regulation effects. The immune microenvironment modulated by LUT@ZIF-8/GelMA hydrogel scaffolds facilitated osteogenic differentiation of BMSCs. Furthermore, in vivo experiments confirmed the osteogenic and inflammatory regulation capabilities of the LUT@ZIF-8/GelMA hydrogel scaffolds. In conclusion, the 3D bioprinted LUT@ZIF-8/GelMA hydrogel scaffolds exhibit osteoimmunomodulatory properties, presenting a promising strategy for the treatment of bone defects.

The opportunistic pathogen Pseudomonas aeruginosa primarily causes infections in immunocompromised individuals. Luteolin, a natural flavonoid, is widely present in plants, which exerts various pharmacological activities, including anti-inflammatory and antimicrobial activities.

This study aimed to explore the therapeutic efficacy of luteolin and the underlying molecular mechanisms in treating the P. aeruginosa-induced acute pneumonia.

Network pharmacology was utilized to identify the core targets of luteolin for treating acute P. aeruginosa pneumonia. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to dissect the potential effects of luteolin and the involved signaling pathways. Surface plasmon resonance (SPR) assay and molecular docking were employed for studying the binding affinities of luteolin with the key targets. Furthermore, we applied a mouse model of bacterial pneumonia for assessing the therapeutic effects of luteolin in vivo, and an in vitro infection model for specifically investigating the effects of luteolin on macrophages as well as the underlying mechanisms upon P. aeruginosa infection.

Network pharmacology identified TNF, IL-6, EGFR and AKT1 as the key targets of luteolin for treating acute P. aeruginosa pneumonia. Moreover, as revealed by GO and KEGG enrichment analysis, EGFR, MAPK and PI3K/AKT pathways were the potential pathways regulated the P. aeruginosa-induced inflammatory response. According to the in vivo results, luteolin effectively mitigated the P. aeruginosa-induced acute lung injury through reducing the pulmonary permeability, neutrophil infiltration, proinflammatory cytokine production (IL-1β, IL-6, TNF and MIP-2) and bacterial burden in lung tissues, which led to increased survival rate of mice. Furthermore, the luteolin-treated mice had diminished EGFR, PI3K, AKT, IκBα, NF-κB p65, ERK, c-Jun and c-Fos phosphorylation, down-regulated M1 macrophage marker levels (iNOS, CD86 and IL-1β) but up-regulated M2 macrophage marker levels (Ym1, CD206 and Arg1) in lung tissues. Consistently, the luteolin-pretreated macrophages exhibited reduced phosphorylation of these regulatory proteins, diminished proinflammatory cytokine production, and down-regulated expression of M1 macrophage markers, but up-regulated expression of IL-10 and M2 macrophage markers.

luteolin effectively suppressed the inflammatory responses and M1 macrophage polarization through inhibiting EGFR/PI3K/AKT/NF-κB and EGFR/ERK/AP-1 signaling pathways in the treatment of acute P. aeruginosa pneumonia. This study suggests that luteolin could be a promising candidate for development as a therapeutic agent for acute bacterial pneumonia.

Distraction osteogenesis (DO) is a highly effective method for bone regeneration. However, its prolonged treatment duration limits its clinical application. Parathyroid hormone (PTH) can promote distraction osteogenesis, but the underlying mechanism remains unclear. During distraction osteogenesis, macrophages modulate inflammation after phenotypic transition, promoting bone regeneration. PTH is known to affect the expression of specific miRNAs, and miR-155 has been shown to regulate macrophage polarization, with subsequent effects on inflammation. We hypothesized that miR-155 may participate in the osteogenic effect of PTH by regulating macrophage polarization. In this study, we aim to explored the mechanism by which PTH promotes distraction osteogenesis using both in vivo and in vitro models.

Established a rabbit model of mandibular distraction osteogenesis in which histomorphological observations confirmed the osteogenic effects of PTH and the reduced expression of miR-155. In addition, a lipopolysaccharide (LPS)-induced macrophage distraction model was established. ELISA was used to measure the expression of the inflammatory cytokines TNF-α and IL-1β in animal serum and cell supernatants. RT‒qPCR was used to detect the expression of miR-155 and SOCS1, and Western blotting and IHC were used to examine SOCS1 expression and explore its mechanisms. The overexpression of miR-155, the proportion of M1 macrophages was reassessed, and the expressions of SOCS1, TNF-α, and IL-1β were concurrently evaluated.

PTH administration significantly downregulated miR-155 expression in both the rabbit model and in vitro macrophages. This led to an upregulation of SOCS1 expression, which in turn reduced the polarization of M1 macrophages. The levels of TNF-α and IL-1β were also markedly reduced in the PTH-treated groups compared to the control groups. In the distraction zone, histological analysis revealed that the experimental group had better trabecular bone formation, with higher density and maturity of trabeculae compared to the control group. Flow cytometry analysis showed a significant reduction in the proportion of M1 macrophages in PTH-treated cells. The dual-luciferase reporter assay confirmed that miR-155 directly targets SOCS1.

PTH downregulates miR-155 in new bone and macrophages during mandibular DO, increasing SOCS1 expression, reducing M1 macrophages, and enhancing bone regeneration by lowering inflammation.

This study synthesizes carbon dots derived from crude extracts of purple sweet potato (CPP-CDs) and evaluates its anti-inflammatory effects in a lipopolysaccharide (LPS) -induced acute inflammation model. Characterization revealed that CPP-CDs possess a uniform spherical structure and excellent photoluminescent properties. In vitro, CPP-CDs significantly inhibited the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), reduced the accumulation of reactive oxygen species (ROS), suppressed pyroptosis, and facilitated the polarization of macrophages from the M1 phenotype to the M2 phenotype. In vivo, CPP-CDs significantly improved the survival rates of LPS-treated mice, mitigated tissue damage, and suppressed the levels of pro-inflammatory cytokines. Mechanistic studies indicated that CPP-CDs exert anti-inflammatory effects through the inhibition of the TLR4/NF-κB signaling pathway and the modulation of the NLRP3 inflammasome. Additionally, CPP-CDs exhibited excellent biocompatibility, with no significant toxicity observed in mice. This study provides strong evidence supporting the application of CPP-CDs as a novel anti-inflammatory material, highlighting their potential for acute inflammation treatment and expanding the possibilities for the development of carbon-dot-based anti-inflammatory therapies.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract caused by dysfunction of the immune system in genetically susceptible individuals. As current pharmacologic and surgical treatments remain suboptimal, increasing attention has been directed toward exosomes derived from mesenchymal stem/stromal cells (MSCs) as alternative therapeutic approaches. MSCs are multipotent stromal cells that can be isolated from various human tissues such as bone marrow, adipose, umbilical cord and periodontal ligament. Exosomes are cell-derived membrane-bound vesicles enclosing RNAs, proteins, growth factors, and cytokines. Previous studies indicate that the anti-inflammatory, immunomodulatory, and regenerative effects of MSCs are largely mediated by MSC-derived exosomes (MSC-Exos). Therefore, this review outlines current insights into the molecular mechanisms of MSC-Exos in IBD treatment to support the future development of MSC-Exos as a therapeutic strategy, thus providing novel observations into the clinical applications of MSC-Exos in IBD management.

Silicosis is a fibrotic disease caused by prolonged inhalation of silica particles. Signal regulatory protein alpha (SIRPα) and its ligand CD47, key innate immune checkpoints mediating inhibition of phagocytosis, have been reported to regulate organ fibrosis. However, the role of SIRPα/CD47 in silicosis remains unexplored. In this study, a silicosis mouse model was constructed and revealed a significant upregulation of SIRPα and CD47 expression in lung tissue with disease progression. In addition, the expression patterns of SIRPα and CD47 in various silicosis effector cells exhibit distinct cell specificity. Using RRx-001 to block SIRPα/CD47 signaling in mice, we observed a marked reduction in lung injury, decreased collagen deposition, and improved pulmonary function. Mechanistically, blocking SIRPα/CD47 affected T cell activation, macrophage polarization and the expression of pro-inflammatory and pro-fibrotic factors. In vitro, we found that inhibiting SIRPα/CD47 countered the silica-induced suppression of macrophage phagocytosis and induced macrophage polarization towards the M1 phenotype. Additionally, levels of soluble SIRPα and CD47 in the peripheral blood of silicosis patients were significantly higher than those in healthy controls. In summary, this study demonstrates that SIRPα/CD47-mediated immunomodulatory signaling is the driving factor for the progression of silicosis, and this pathway might serve as a therapeutic target for silicosis treatment.

Recurrent spontaneous abortion (RSA) is linked to pro-inflammatory responses driven by macrophage M1 polarization. miR-194-5p can affect the migration and infiltration of macrophages, and significantly inhibit the release of pro-inflammatory cytokines. However, whether miR-194-5p can affect RSA through M1 macrophage-related pathway remains to be further explored. To induce human monocytic leukemia THP-1 into M1 macrophages, PMA and LPS were used. Then detect the effects of transfection with miR-194-5p mimics on the migration, invasion, cell cycle and apoptosis of M1 macrophages. Two databases, DIANA-microT and miRDB, were first used to predict the target gene of miR-194-5p, and TRAF6 was selected as the target gene of miR-194-5p, and then the binding sites of the two were predicted and verified by dual luciferase assay. Transfection of inhibitors, with or without TRAF6 siRNA (si-TRAF6), was performed on M1 macrophages to assess changes in viability, migration, aggressiveness, cell cycle, and apoptosis, as well as TRAF6, NF-κB, and Wnt5a mRNA and protein levels. Compared with the miR-NC group, transfection with the miR-194-5p mimic significantly reduced the viability, migration, and invasion abilities of M1 macrophages, arrested them in the S phase, and promoted apoptosis. miR-194-5p bound to TRAF 3'UTR-WT and reduced the viability, migration ability, and aggressiveness of M1 macrophages, increased apoptosis, and blocked the S phase. miR-194-5p negatively regulated TRAF6, resulting in decreased mRNA and protein levels of NF-κB and Wnt5a. miR-194-5p inhibitors and mimics had opposite effects, but miR-194-5p inhibitor effects could be reversed by si-TRAF6. There is a close association between RSA and M1 macrophage polarization. Furthermore, miR-194-5p inhibits the NF-κB and Wnt5a signaling pathways by negatively regulating TRAF6, thereby impeding the function of M1 macrophages and affecting the occurrence of RSA. These findings provide new therapeutic targets for the prevention, diagnosis, and treatment of RSA.

The aim of this study was to elucidate the causal relationship between immunophenotypes and heart failure (HF) using bidirectional Mendelian randomization (MR) analysis. Summary-level data for HF and immunophenotypes were obtained from public genome-wide association study data. Five robust MR methods were employed to delineate the causal effects between the 2. Further analyses included horizontal pleiotropic analysis, Cochran Q analysis, MR-Egger intercept test, and leave-one-out analysis. Finally, we used the screened immunophenotypes as outcomes and HF as exposure for reverse MR analyses. Eight immunophenotypes demonstrated an increased risk of HF, including immunoglobin D+ (IgD+) CD38br absolute cell (AC); double positive (CD4+CD8+) %leukocyte; CD28- CD127- CD25++ CD8br %T cell; CD28- CD127- CD25++ CD8br %CD8br; CD28+ CD45RA+ CD8br %T cell; CD19 on IgD+ CD38br; CD27 on IgD- CD38dim; CD45 on lymphocyte. Conversely, 7 immunophenotypes exhibited a reduced risk of HF, including Activated Treg AC; Im myeloid-derived suppressor cell %CD33dim human leukocyte antigen DR- (HLA DR-) CD66b-; CD33dim HLA DR+ CD11b+ %CD33dim HLA DR+; CD20 on IgD- CD38dim; side scatter-A (SSC-A) on CD14+ monocyte; SSC-A on HLA DR+ natural killer cell; CD11b on CD14+ monocyte. Importantly, we did not find any horizontal multidimensional outliers, genetic heterogeneity, directional pleiotropy, or a single nucleotide polymorphism that determines ultimate causality. The results of the reverse MR analysis were not statistically significant. In this study, the genetic correlation between 15 immunophenotypes and HF was revealed by MR analysis, which provides a reference for future clinical treatment.

The abuse of immunosuppressants causes damage to the immune system, while the pathological proliferation and translocation of symbiotic Candida albicans can result in abdominal infection in immunocompromised people. In this study, we established a mouse peritoneal C. albicans infection model and investigated the effects of preventive application of Sodium New Houttuyfonate (SNH) by analyzing the proportion of immune cells, polarization of peritoneal macrophages, changes in fungal tissue load, and histology, and the data showed prophylactic SNH administration yields a double anti-infection effect in phagocytosis and regulation of immunity according to the immune inflammatory states of the body. In vitro, neutral red, colony counting, cytometric bead array, RT-qPCR, western blot, inhibitor treatment, and detection of reactive oxygen species (ROS) and nitric oxide (NO) production on RAW264.7 macrophages showed SNH can stimulate the production of tumor necrosis factor-alpha (TNF-α) and CC motif ligand 2 (CCL2) and the release of ROS and NO through a TLR2/p38/NF-κB pathway. Taken together, our data provide an innovative insight into the prevention use of exogenous SNH for the treatment of C. albicans infection.

The aim of this study was to explore the therapeutic effect of berberine chloride (BBR) on postoperative ileus (POI) and unravel the mechanism by which BBR alleviates POI.

A POI model was established in mice through intestinal manipulation (IM). The impact of BBR on gastrointestinal motility and inflammation was assessed 24 h post-IM by evaluating gastrointestinal transit (GIT), cytokine expression, leukocyte infiltration and macrophage polarization in POI mice. Network pharmacology analysis was employed to explore the mechanism of BBR's action on POI. Bone marrow derived macrophages (BMDMs) were isolated for in vitro culture, and the influences of BBR on cell viability, cytokine production, macrophage polarization and the PI3K/AKT signaling pathway in BMDMs were evaluated.

BBR administration significantly attenuated the intestinal motility dysfunction, reduced leukocyte infiltration, inflammatory mediator expression, and M1 macrophage polarization in the intestinal muscularis of POI mice. Network pharmacology analysis indicated that BBR may exert anti-inflammatory effects on POI via the PI3K/AKT signaling pathway. In vitro studies demonstrated that BBR inhibited macrophage activation and M1 macrophage polarization without affecting M2 macrophage polarization. Further analysis showed that BBR inhibited M1 macrophage polarization by downregulating PI3K expression and AKT phosphorylation, while 740 Y-P, a PI3K pathway agonist, reversed this effect.

BBR markedly alleviates manipulation-induced intestinal inflammation in muscular tissue and restores intestinal transit in POI mice. Mechanistically, BBR exerts anti-inflammatory effects on POI by inhibiting M1 macrophage polarization via regulating the PI3K/AKT signaling pathway.

Knee osteoarthritis (OA) is a common degenerative joint disease that affects millions of people worldwide. Inflammation is one of the key pathogenic factors of knee OA. However, the causal relationship between immune cells and knee OA development remains unclear. Herein, we used Mendelian randomization (MR) analysis to evaluate causal relationship between 731 immune cells and knee OA. Several methods were applied to ensure the robustness of our results, including inverse-variance weighted (IVW), simple mode, weighted median, weighted mode, and MR-Egger. We found that 23 immune cell phenotypes were causally associated with knee OA (P < 0.05), including various subpopulations of B cells, T cells, TBNK (T cells, B cells, Natural Killer cells) and monocytes, which was confirmed by heterogeneity, sensitivity, and pleiotropy tests. B cells had dominant effects on OA development, and specifically, our findings suggest that BAFF-R in IgD + CD38- unswitched memory B cells may have a protective role, whereas CD25 in IgD + CD24 + B cells appears to be associated with increased risk, pending further validation. Moreover, a higher population of regulatory T (Treg) cells indicated a higher risk of OA and reversely, OA could induce Treg differentiation. Collectively, our study identified several immune cells that were closely related to OA development, which provided novel insights into the pathogenesis of OA and therapeutic targets for OA treatment.

The incidence of allergic diseases has been increasing annually, severely affecting the quality of life of patients. With the growing recognition of traditional medicine, acupuncture, an ancient Chinese therapeutic method, has gradually gained attention for its potential in immune modulation. Studies have shown that macrophages play a crucial role in the development of allergic diseases, and acupuncture may influence allergic reactions by modulating the function of macrophages. This article aims to systematically evaluate the regulatory effects of acupuncture on macrophages in allergic diseases and the corresponding mechanisms. It analyzes existing research findings and explores the clinical application prospects of acupuncture in this context. By understanding how acupuncture affects the activation, secretion, and role of macrophages in immune responses, we hope to provide new insights and directions for the treatment of allergic diseases.

The enhanced M1 macrophage activation and proportion significantly promote the progression of renal fibrosis in the unilateral ureteral obstruction (UUO) model, while the underlying mechanisms need to be further studied. Here, we examined whether or not endoplasmic reticulum (ER) stress contributed to M1 macrophage activation and the mechanisms in this process. In the UUO mouse model, the proportion of M1 macrophages could be significantly increased in the early renal fibrosis, with the ER stress activated. The inhibitor of ER stress (4-PBA) significantly suppressed the activation of M1 macrophages and alleviated the renal fibrosis in the UUO mouse model. Furthermore, the renal fibrosis could be relieved after the administration of IRE1α inhibitor (4μ8C), with the downregulation of ER stress and M1 macrophage activation. Mechanistically, ER stress-enhanced activation of M1 macrophages was regulated through the IRE1α/XBP1s-p38 MAPK pathway. IRE1α-deficient macrophages could alleviate the renal fibrosis in the UUO mouse model. Thus, our findings suggest that the ER stress pathway regulates M1 macrophage activation in the UUO model, which provides a novel therapeutic approach for renal fibrosis.

The rapid advancement of implantable biomedical materials necessitates a comprehensive understanding of macrophage interactions to optimize implant immunocompatibility. Macrophages, key immune regulators, exhibit phenotypic plasticity by polarizing into pro-inflammatory (M1) or anti-inflammatory (M2) subtypes. Conventional phenotyping techniques, such as flow cytometry and immunostaining, provide insights but have limitations related to fixation and endpoint analysis. This study presents a high-throughput, label-free macrophage phenotyping approach integrating AI-driven image classification with quantitative phase imaging (QPI). THP-1-derived macrophages were differentiated into M0, M1, M2a, and M2c phenotypes, and their morphological and refractive index properties were analyzed using QPI. Although QPI alone could not fully distinguish phenotypes, deep learning models, including GoogLeNet, ShuffleNet, VGG-16, and ResNet-18, were evaluated, with ResNet-18 achieving over 90% accuracy. Additionally, macrophage responses to collagen coatings (types I, III, and IV) were assessed using machine learning-based phenotyping and cytokine profiling. Collagen I induced an M1 response, collagen III supported a balanced M1/M2 profile, and collagen IV promoted a controlled immune environment. These findings demonstrate the potential of AI-driven QPI as a non-invasive tool for macrophage characterization, offering insights into biomaterial immunocompatibility and informing implant design strategies.

SLP65/SLP76, Csk-interacting membrane protein (SCIMP), is a membrane protein plays a crucial role in the regulation of macrophage polarization. This study aimed to investigate the mechanism of SCIMP-mediated M1 polarization in liver macrophages and ischemia-reperfusion injury (IRI) in liver transplantation.

Mice underwent orthotopic liver transplantation. In in vivo experiments, mice were divided into the Sham group, LT group, LT+Scramble group, LT+SCIMP (-) group, and LT+ERK1/2 (-) group, and SCIMP or ERK1/2 knockdown was performed using AAV-Erk1/2-RNAi-F4/80-EGFP and AAV-SCIMP-RNAi-F4/80-EGFP. In the subsequent in vitro experiments with primary cells, macrophages were divided into the Ctrl group, H/R group, H/R+Scramble group, H/R+SCIMP (-) group, and H/R+ERK1/2 (-) group, with SCIMP knockdown achieved using siRNA. Immunoprecipitation (IP) was used to detect the interaction between TLR4 and Erk1/2. Liver damage was detected by Hematoxylin and eosin (HE) staining. Polarization was detected by western blot (WB), RT-PCR, immunohistochemistry (IHC), immunofluorescence technique (IF), enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FC).

Knockdown of SCIMP ameliorated hepatic IRI and liver macrophages M1 polarization. Mechanically, SCIMP promoted the interaction between Erk1/2 and TLR4 in hypoxia/reoxygenation (H/R)-induced liver macrophages, while the inhibition of Erk1/2 reduced liver macrophages M1 polarization and liver IRI.

SCIMP promotes hepatic ischemia-reperfusion injury by activating TLR4/Erk1/2-mediated liver macrophages M1 polarization, which might become a potential therapeutic target in clinic.