Acute inflammation, characterized by a rapid influx of neutrophils, is a protective response that can lead to chronic inflammatory diseases when left unresolved. We previously showed that secretion of LTB4-containing exosomes via nuclear envelope-derived multivesicular bodies is required for effective neutrophil infiltration during inflammation. Here we report that the co-secretion of these exosomes with nuclear DNA facilitates the resolution of the neutrophil infiltrate in a mouse skin model of sterile inflammation. Activated neutrophils exhibit rapid and repetitive DNA secretion as they migrate directionally using a mechanism distinct from suicidal neutrophil extracellular trap release and cell death. Packaging of DNA in the lumen of nuclear envelope-multivesicular bodies is mediated by lamin B receptor and chromatin decondensation. These findings advance our understanding of neutrophil functions during inflammation and the physiological relevance of DNA secretion.

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.

Fibrosis, characterized by abnormal deposition of structural proteins, is a major cause of tissue dysfunction in chronic diseases. The disease burden associated with progressive fibrosis is substantial, and currently approved drugs are unable to effectively reverse it. Immune cells are increasingly recognized as crucial regulators in the pathological process of fibrosis by releasing effector molecules, such as cytokines, chemokines, extracellular vesicles, metabolites, proteases, or intercellular contact. Therefore, targeting the immune microenvironment can be a potential strategy for fibrosis reduction and reversion. This review summarizes the recent advances in the understanding of the immune microenvironment in fibrosis including phenotypic and functional transformations of immune cells and the interaction of immune cells with other cells. The novel opportunities for the discovery and development of drugs for immune microenvironment remodeling and their associated challenges are also discussed.

Macrophages play a central role in maintaining tissue homeostasis and in surveillance against pathogens and disease. In the lung, they can adopt either proinflammatory or anti-inflammatory states depending on the nature of the stimulus. As the predominant immune cells in both the lung tumor microenvironment and in sites of lung infection, the functional plasticity of macrophages makes them key players in determining disease outcome. Accurately defining their inflammatory profiles offers an opportunity to reprogram infection-associated macrophages towards enhanced tumor-killing phenotypes. This review explores how acute inflammation can drive macrophage-mediated antitumor immunity and highlights key molecules and signaling pathways that may be leveraged to therapeutically modulate macrophage function.

Osteoarthritis (OA) remains a leading cause of disability worldwide, with no disease-modifying therapies currently available for treatment. The infrapatellar fat pad (IFP) harbors mesenchymal stem/stromal cells (MSC) with potent immunomodulatory and regenerative properties, making them a promising candidate for OA treatment. A growing body of evidence suggests that the therapeutic effects of MSC are largely mediated by their extracellular vesicles (EVs), which carry bioactive cargo that modulates inflammation and tissue repair. However, optimizing MSC-derived EVs as a cell-free therapeutic approach requires an in-depth understanding of how culture conditions and inflammatory/hormonal priming influence their functional properties. In this study, IFP-MSC were expanded in regulatory-compliant human platelet lysate (HPL) and xeno-/serum-free (XFSF) media and primed with an inflammatory/fibrotic cocktail (TIC) with oxytocin (OXT) to assess the impact on their immunophenotypic profile and EV cargo. The immunophenotype confirmed that TIC+OXT-primed MSC retained key immunomodulatory surface markers, while EV characterization verified the successful isolation of CD63+/CD9+ vesicles. Pathway enrichment analysis of both HPL- and XFSF- TIC+OXT EVs cargo identified key miRNAs associated with immune regulation, tissue repair, and anabolic signaling. Functional assays revealed that TIC+OXT EVs promoted M2-like anti-inflammatory macrophage polarization and exhibited chondroprotective properties in chondrocytes/synoviocytes inflammatory osteoarthritic assay. These findings highlight the therapeutic potential of TIC+OXT-primed IFP-MSC-derived EVs as immunomodulatory and chondroprotective agents, offering a promising strategy for OA treatment through a clinically viable, cell-free approach.

Parkinson's disease (PD), the second most common neurodegenerative disease with notable clinical heterogeneity, has Parkinson disease dementia (PDD) that severely impacts patients' quality of life. As no effective treatment exists, this study aimed to find potential drug targets for PD cognitive disorders.

Two-sample Mendelian randomization (MR) and transcriptome analysis were used to identify PD biomarkers. Protein-protein interaction (PPI), gene ontology (GO), and KEGG pathway analyses explored biological effects. A nomogram model was developed.

76 Mendelian randomization genes (MRGs) from MR and 1771 differentially expressed genes (DEGs) from the transcriptome were obtained. Three significant shared DEGs (S-DEGs) were identified, with USP8 and STXBP6 having strong diagnostic value for PDD. The nomogram model with these two genes showed enhanced predictive ability. These genes had physical interactions, co-localization, and correlated with ODC and NEU immune cells. USP8 was linked to five diseases, and STXBP6 to one.

USP8, STXBP6, and immune cells (ODC and NEU) associated with PDD were identified, offering new insights into PD progression.

Macrophage polarization plays a pivotal role in immune homeostasis and disease progression across inflammatory, neoplastic, and metabolic disorders. Saponins, which are natural compounds with steroidal/triterpenoid structures, demonstrate therapeutic potential through immunomodulatory, anti-inflammatory, and anti-tumor activities. This study aims to highlight the potential of key saponins-such as ginsenosides, astragaloside IV, dioscin, platycodin D, pulsatilla saponins, and panax notoginseng saponins-in modulating macrophage polarization and enhancing conventional therapies, particularly in oncology. We conducted structured searches in PubMed, Google Scholar, and SciFinder (2013-2024) using controlled vocabulary, including "saponins," "macrophage polarization," and "therapeutic effects." Our findings demonstrate that saponins significantly modulate immune responses and improve treatment efficacy. However, clinical translation is hindered by challenges such as poor bioavailability and safety concerns, which limit systemic exposure and therapeutic utility. To overcome these barriers, innovative delivery strategies, including nanoemulsions and engineered exosomes, are essential for enhancing pharmacokinetics and therapeutic index. Future research should prioritize elucidating the molecular mechanisms underlying saponin-mediated macrophage polarization, identifying novel therapeutic targets, and optimizing drug formulations. Addressing these challenges will enable the restoration of immune balance and more effective management of diverse diseases.

Retained placenta (RP) is a common reproductive disorder with complex etiology and pathogenesis, affecting approximately 8% of dairy cows during the periparturient period. Macrophages constitute 20-25% of all leukocytes at the maternal-fetal interface and coordinate several processes critical for fetal membrane expulsion, including tissue remodeling, induction of apoptosis in damaged cells, and immune activation. This study aimed to investigate the morphological changes at the maternal-fetal interface, as well as the quantity, distribution, and polarization of caruncle macrophages in cows with and without RP. Furthermore, we discuss the potential association between macrophage alterations and histopathological changes in placental tissue of RP cows. A total of 80 Holstein dairy cows (parity, 2-4) were enrolled in this study. Blood samples were collected at -7 d before the expected calving date (-7D), at calving (0h), at 12h postpartum (12h) and at 7 d postpartum (7D). Placental tissue samples were collected within 30 min after parturition. Based on whether the placental membranes were expelled within 12 h postpartum, cows were classified retrospectively into normal expulsion (NE) (n = 6) and RP (n = 6) groups. Picrosirius red staining, along with elevated mRNA and protein levels of Collagen III, indicated enhanced collagen fiber deposition in caruncle tissue. In addition, the mRNA expression of matrix metalloproteinases (MMP-2 and MMP-9) was downregulated in RP tissues, while TIMP-1 was upregulated. Compared with normal expulsion cows, the apoptosis index, as well as the protein and mRNA levels of pro-apoptotic factors (BAX, Caspase-3, Caspase-8) were lower in cows with RP, and the anti-apoptotic factor (BCL2) was higher, indicating reduced apoptosis in the caruncle tissue from RP cows. In both the serum and tissues, we observed lower levels of chemotactic factors (CXCL1 and MCP-1) in RP cows, alongside increased IL-10 (an immunosuppressive factor) and decreased IL-1β (an immune-stimulatory factor). The downregulated protein and mRNA abundance of the macrophage marker CD68, consistent with reduced presence of CD68+ cells observed through immunofluorescence, revealed low numbers of caruncle macrophages in cows with RP. Further, the caruncles tissue of RP cows displayed significant alterations in the distribution of CD68+ macrophages, with reduced infiltration into trophoblast cells. Regarding macrophage phenotypic changes in RP cows, the greater protein and mRNA expression of M2 polarization markers (CD206, IL-10, IL-6, and TGF-β) along with greater numbers of CD206+/CD68+ cells detected through immunofluorescence indicated that macrophage polarization phenotype in the caruncles of RP cows shifted predominantly toward M2 phenotype. In contrast, RP cows exhibited lower protein and mRNA levels of M1 polarization markers (CD86, iNOS, IL-1β, and NF-κB), as well as reduced numbers of CD86+/CD68+ cells. Overall, caruncle tissues from RP cows were characterized by a reduced macrophage population with a predominant M2 phenotype. Alterations in the quantity and polarization state of macrophages at the maternal-fetal interface may lead to reduced immune cell trafficking into the caruncle, thus impairing the apoptotic and proteolytic processes essential for placental expulsion.

Abnormalities in inflammation resolution function are intimately linked to chronic inflammation, and proresolution therapies may offer novel opportunities for IBD treatment. Developmental endothelial locus 1 (DEL-1), a natural modulator of tissue immunity and inflammation resolution, has not been studied in IBD.

We aimed to investigate the expression and functions of DEL-1 in IBD.

Assessment of DEL-1 expression in patients, murine models, and cellular levels. To explore the effects of DEL-1 in the acute and recovery phases of inflammation, overexpression plasmids, adeno-associated viruses for DEL-1 knockdown, and DEL-1-Fc fusion proteins were administered to cells and mice. Additionally, the potential mechanism of DEL-1 in IBD was demonstrated using flow cytometry, RNA-Seq, ChIP, dual-luciferase reporter assays and 16S rRNA.

DEL-1 levels were significantly reduced in IBD patients, colitis mice and macrophages, while the levels increased with inflammation to resolve. Transfection with DEL-1 overexpression plasmid or DEL-1-Fc intervention reduces levels of inflammatory cytokines in both phases and upregulates reparative gene levels in the recovery phase. DEL-1 knockdown inhibits inflammation resolution of colitis. Mechanistically, we demonstrated that DEL-1 inhibits Cmpk2-dependent mtDNA synthesis, thereby inhibiting the cGAS-STING pathway to ameliorate intestinal inflammation. Moreover, DEL-1 promotes reparative macrophage transition in the repair model of colitis. Spi1 was identified as a transcription factor that regulates Cmpk2 and the reparative gene Il10. Intervention with overexpression plasmid of Spi1 or Cmpk2 or the STING agonist DMXAA reverses the effects of DEL-1. In parallel, DEL-1 also inhibits neutrophil recruitment, repairs the intestinal barrier, and improves intestinal microbiota dysbiosis.

We report the first demonstration that DEL-1 significantly ameliorates colonic inflammation in colitis mice. Our findings elucidate a novel mechanism wherein DEL-1 exerts its protective effects by suppressing the Cmpk2-cGAS-STING pathway and promoting reparative macrophage transition. These results collectively position DEL-1 as a promising therapeutic avenue for IBD.

Monocytes differentiate into macrophages (Mφs) to facilitate lung metastasis, but the monocyte-to-Mφ transition during this process is not well understood. To investigate, we performed bulk RNA sequencing on Mφs isolated from the lungs of mice bearing Lewis lung carcinoma tumors and from naive lungs. Our results showed impaired differentiation of monocytes into major histocompatibility complex (MHC) class II+ Mφs, with an upregulation of PGE2-inducible genes, including Arg1, in tumor-associated Mφs (TAMs). In vitro experiments confirmed that prostaglandin E2 (PGE2) inhibits the differentiation of MHC class II+ Mφs while promoting Arg1+ Mφs via the E prostanoid 2 (EP2) receptor, accompanied by DNA methylation. Whole-genome bisulfite sequencing revealed that PGE2-EP2 signaling drives the hypermethylation and downregulation of gene sets related to myeloid cells in non-neoplastic tissues. Our study highlights PGE2-EP2-driven DNA methylation in the monocyte-to-TAM transition, suggesting potential therapeutic avenues for lung metastasis.

Fungal keratitis is a severe vision-threatening corneal infection with a prognosis influenced by fungal virulence and the host's immune defense mechanisms. However, there is still a lack of effective drugs that attenuate fungal virulence while relieving the inflammatory response caused by fungal keratitis.

Finding an effective treatment to solve these problems is particularly important.

We synthesized Zeolitic imidazolate framework-90 (ZIF-90) by water-based synthesis method and characterized it. In vitro experiments included mycelium electron microscopy, Cell Counting Kit-8 (CCK-8), and Enzyme-linked immunosorbent assay (ELISA). These trials verified the disruptive effects of ZIF-90 on morphology, cell membrane, cell wall, and biofilm formation of Aspergillus fumigatus (A. fumigatus). These experiments also demonstrated the impact of ZIF-90 on the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Moreover, the effect of ZIF-90 on mitochondrial reactive oxygen species (mtROS) of cells and fungi was verified by MitoSOX Red Mitochondrial Superoxide Indicator (MitoSOX). In vivo, corneal toxicity test, establishment and treatment of mycotic keratitis mouse model, and immunofluorescence staining were used to evaluate the efficacy of ZIF-90 in the procedure of fungal keratitis. In addition, to investigate whether the metal-ligand zinc and the organic ligand imidazole acted as essential factors in ZIF-90, we investigated the in vitro antimicrobial and anti-inflammatory effects of ZIF-8, ZIF-67 and Metal-Organic Frameworks-74 (Zn) (MOF-74 (Zn)) by Minimum Inhibitory Concentration (MIC) and ELISA experiments.

ZIF-90 has therapeutic effects on fungal keratitis, which could break the protective organelles of A. fumigatus, such as the cell wall. In addition, ZIF-90 can also be targeted to increase the amount of mtROS in fungi and promote apoptosis of macrophages. The results demonstrated that both zinc ions and imidazole possessed antimicrobial and anti-inflammatory effects. In addition, ZIF-90 exhibited better antifungal properties than ZIF-8, ZIF-67, and MOF-74 (Zn).

High fibrosis of the tumor microenvironment (TME) not only impedes the effective infiltration of T cells but also serves as a physical barrier to inhibit the penetration of chemotherapy drugs. Triple-negative breast cancer (TNBC) is characterized by significant infiltration of tumor-associated macrophages (TAMs) and high fibrosis. However, the mechanism of high fibrosis in such tumors is still under debate.

We first investigated the correlation between tumor-derived osteopontin (OPN) and tumor fibrosis as well as TAM enrichment using a tumor model characterized by OPN genetic inactivation or overexpression. We further compared the effects of macrophage depletion on tumor fibrosis in mice bearing TNBC tumors (4T1WT or 4T1Spp1 - KO). To elucidate the mechanism by which TAMs promote tumor fibrosis, we evaluated their potential to recruit cancer-associated fibroblasts (CAFs) through in vitro migration assays and compared the production of transforming growth factor-beta 1 (TGFβ1) among different TAM subpopulations.

Our study revealed that OPN secretion by tumor cells correlates positively with both tumor fibrosis and TAM enrichment. Specifically, within the enriched TAM population, Ly6C+CD206- TAMs recruit CAFs via CCL5 secretion, while Ly6C-CD206high TAMs secrete TGFβ1 to activate CAFs. Blocking the tumor cell-derived OPN can effectively prevent tumor fibrosis.

This study shows that tumor-derived OPN primarily drives TAM enrichment in mouse cancer model, indirectly promoting tumor fibrosis through Ly6C+CD206-/low and Ly6C-CD206high TAMs. Our findings have potential application in preventing tumors from excessive fibrosis and enhancing the efficacy of immunotherapy and chemotherapy.

Inflammation drives the initiation and progression of pulmonary hypertension (PH). Platelets, increasingly recognized as immune cells, are activated and increased in the lungs of patients with PH. Platelet activation leads to the release of α-granule chemokines, many of which are implicated in PH. We hypothesized that hypoxia-induced secretion of platelet α-granule-stored proteins and PH would be prevented in Neurobeachin-like 2 knockout (Nbeal2-/-) α-granule-deficient mice. Wild-type (WT) and Nbeal2-/- mice were maintained in normoxia or exposed to 10% hypobaric hypoxia for 3, 14, 21, or 35 days. We observed macrothrombocytopenia, increased circulating neutrophils and monocytes, and increased lung interstitial macrophages (IMs) in Nbeal2-/- mice at baseline. Hypoxia-induced platelet activation was attenuated, and hypoxia-induced increase in lung platelet factor 4 (PF4) and platelets was delayed in Nbeal2-/- mice compared with in WT mice. Finally, although pulmonary vascular remodeling (PVR) and PH were attenuated at day 21, Nbeal2-/- mice were not protected against hypoxia-induced PVR and PH at day 35. Although this mutation also affected circulating monocytes, neutrophils, and lung IMs, all of which are critical in the development of experimental PH, we gained further support for the role of platelets and α-granule proteins, such as PF4, in PH progression and pathogenesis and made several observations that expand our understanding of α-granule-deficient mice in chronic hypoxia.

Biological hydroxyapatite (BHA) has been extensively employed in alveolar socket preservation, yet its clinical application is often compromised by delayed bone healing triggered by macrophage-mediated pro-inflammatory responses. Building upon our previous work, in which we successfully incorporated fluorine into BHA to develop fluorinated biogenic hydroxyapatite (FBHA) with superior physicochemical and biological properties, this study systematically investigated the effects of fluorine doping on macrophage-mediated osteoimmunomodulation and socket bone healing. The synthesized FBHA was characterized using SEM, EDS, and fluoride ion release assays to confirm fluorine incorporation. In macrophage co-culture models, FBHA demonstrated significant advantages over BHA, effectively suppressing iNOS and TNFα gene expression, reducing NO release, and inhibiting phagocytic activity in M1 macrophages. RNAseq analysis revealed that the M1 phenotype suppression might be mediated through enhanced cellular antioxidant activity. Moreover, in macrophage-conditioned microenvironments, FBHA significantly upregulated osteogenic gene expression and ALP activity of pre-osteoblasts. In vivo experiments demonstrated FBHA's superior performance in alveolar ridge preservation, especially in new bone formation and mineralization inside sockets. Fluorine doping significantly boosted socket bone healing via suppressing the inflammatory response of macrophages and enhancing osteogenic differentiation of pre-osteoblasts. These findings provide valuable insights into the development of next-generation biomaterials for alveolar socket preservation.

The immune microenvironment plays a critical role in tumor growth and development. Immune activation within the tumor microenvironment is dynamic and can be modulated by tumor intrinsic and extrinsic signaling. The RON receptor tyrosine kinase is canonically associated with growth signaling and wound healing, and this receptor is frequently overexpressed in a variety of cancers. Epithelial cells, macrophages, dendritic cells, and fibroblasts express RON, presenting an important axis by which RON overexpressing tumors influence the tumor microenvironment. This review synthesizes the existing literature on the roles of tumor cell-intrinsic and -extrinsic RON signaling, highlighting areas of interest and gaps in knowledge that show potential for future studies.

Pulmonary diseases, arising from infections caused by bacteria, fungi, and viruses, or stemming from underlying genetic factors are one of the leading causes of mortality in humans, accounting for millions of deaths every year. At the onset of pulmonary diseases, crucial roles are played by phagocytic immune cells, particularly tissue-resident macrophages, in regulating the immune response at the mucosal barrier. Recent strides have illuminated the pivotal role of host bioenergetics modulated by metabolites derived from both pathogens and hosts in influencing the pathophysiology of major organs. Their influence extends to processes such as the infiltration of immune cells, activation of macrophages, and the polarization phenomenon. Furthermore, host-derived metabolites, such as itaconate, contribute to the promotion of anti-inflammatory responses, thereby preventing immunopathology and facilitating the preservation of mucosal niches to thrive for the long-term. This review explores recent advancements in the field of immunometabolism, with a particular emphasis on the intricacies of disease progression in pulmonary infections caused by bacteria such as P. aeruginosa, M. tuberculosis and S. aureus and fungi like C. albicans.

As the site of gas exchange, the lung is critical for organismal survival. It is also subject to continual environmental insults inflicted by pathogens, particles, and toxins. Sometimes, these insults result in structural damage and the initiation of an innate immune response. Operating in parallel, the immune response aims to eliminate the threat, while the repair process ensures continual physiological function of the lung. The inflammatory response and repair processes are thus inextricably linked in time and space but are often studied in isolation. Here, we review the interplay of innate immune cells and nonimmune cells during lung insult and repair. We highlight how cellular cross talk can fine-tune the circuitry of the immune response, how innate immune cells can facilitate or antagonize proper organ repair, and the prolonged changes to lung immunity and physiology that can result from acute immune responses and repair processes.

The decrease in fibroblast collagen is a primary contributor to skin aging. Lactate can participate in collagen synthesis through lysine lactylation by regulating gene transcription. However, the precise mechanism by which lactate influences collagen synthesis requires further investigation. This study demonstrates that the depletion of macrophages mitigates the stimulating effect of lactate on collagen synthesis in fibroblasts. Through joint CUT&Tag and RNA-sequencing analyses, a feedback loop between H4K12 lactylation (H4K12la) and histone deacetylase 3 (HDAC3) in macrophages that drives lactate-induced collagen synthesis are identified. Macrophages can uptake extracellular lactate via monocarboxylate transporter-1 (MCT1), leading to an up-regulation of H4K12la levels through a KAT5-KAT8-dependent mechanism in response to Poly-L-Lactic Acid (PLLA) stimulation, a source of low concentration and persistent lactate, thereby promoting collagen synthesis in fibroblasts. Furthermore, H4K12la is enriched at the promoters of TGF-β1 and TGF-β3, enhancing their transcription. Hyperlactylation of H4K12la inhibits the expression of the eraser HDAC3, while the activation of HDAC3 reduces H4K12la in macrophages and suppresses collagen synthesis in fibroblasts. In conclusion, this study illustrates that macrophages play a critical role in lactate-induced collagen synthesis in the skin, and targeting the lactate-H4K12la-HDAC3-TGF-β axis may represent a novel approach for enhancing collagen production to combat skin aging.

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.

Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.

Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8high dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.

Metabolically unhealthy obesity (MUO) poses significant health risks, including increased susceptibility to type 2 diabetes and cardiovascular diseases. Hesperetin is a key bioactive compound found in citrus fruits. Previous studies have shown that hesperetin can correct metabolic abnormalities and mitigate the progression of various metabolic disorders, but the underlying mechanisms remain unclear. Here, we explored the impact of hesperetin on MUO using ob/ob mice and investigated its potential pharmacological mechanisms. The present data indicated that administration of hesperetin for 12 weeks led to notable improvements in metabolic parameters, including reduced fasting blood glucose, fasting insulin levels, and the HOMA-IR index in ob/ob mice. Glucose and insulin tolerance tests demonstrated that hesperetin effectively enhanced insulin sensitivity, with high-dose effects comparable to metformin. Hesperetin treatment decreased inguinal white adipose tissue (iWAT) weight and improved insulin signaling by increasing AKT phosphorylation. Additionally, it reduced the expression of pro-inflammatory cytokines (Il-6 and Il-1β), chemokine Ccl2 and its receptor Ccr2, and macrophage activation markers Nos2 and Ptgs2 within iWAT of ob/ob mice, likely by inhibiting NF-κB activation and macrophage-mediated inflammation. In vitro studies further confirmed hesperetin's anti-inflammatory effects in LPS-stimulated macrophages, where it suppressed cytokine production and NF-κB signaling. Hesperetin also impaired CCL2-induced macrophage chemotaxis, reducing migration velocity and distance. Mechanistically, hesperetin directly interacts with and inhibits IKKβ kinase activity by binding to key residues (LEU21, VAL465, CYS99, and GLU97) and stabilizing the complex, as demonstrated by molecular docking and molecular dynamics simulations. These findings underscore hesperetin's therapeutic potential in mitigating metabolically unhealthy obesity, obesity-induced insulin resistance, and inflammation through direct modulation of the IKKβ and NF-κB pathways.

This study explores the complex mechanisms between Rheumatoid Arthritis (RA) and cellular senescence, with a focus on the role of four key genes (MMP1, CCL7, CXCL1, HK3) identified through transcriptome analysis in the GEO database. These genes are closely related to IL-17 signalling and the pathogenesis of RA. In a macrophage senescence model induced by hydrogen peroxide (H2O2) and bleomycin (BLM), quantitative real-time PCR (qRT-PCR) and Western blot confirmed the significant upregulation of these genes and an increase in the secretion of the cytokine IL-17, which promotes an inflammatory environment for the polarization of macrophages to M1. When co-cultured with mouse synovial fibroblasts (MSF), MSF showed enhanced vitality and increased invasiveness, indicating a key role for these genes in the progression of RA. Additionally, HK3, less reported in RA, when its expression is knocking down, lactate secretion and lactylation modification at lysine 14 of histone H3 in macrophages were reduced, leading to a change in macrophage polarity. The study concludes that the altered polarity of senescent macrophages drives the proliferation and invasion of MSF, significantly promoting the development of RA and providing insights into the pathophysiology of RA.

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Subclinical ketosis (SCK) is highly prevalent and easily overlooked, with insidious and slow progression of hepatic injury, often characterized by an imbalance in immune homeostasis. In nonruminants, macrophage polarization plays an important regulatory role in hepatic lipid accumulation, fibrosis, and inflammatory processes. Thus, we aimed to investigate the status of hepatic macrophage polarization in SCK cows and to corroborate its association with liver injury and inflammation. Twelve Holstein dairy cows (parity 2-4) were selected, and liver biopsy and blood were collected on the second week postpartum (10-14 d DIM). On the basis of serum beta-hydroxybutyric acid (BHBA) concentrations, selected cows were categorized into healthy (n = 6; BHBA <1.0 mM) and SCK (n = 6; 1.2 mM ≤ BHBA < 3.0 mM) groups. Serum biochemical parameters were measured using an automatic biochemical analyzer, which indicated higher serum levels of BHBA and nonesterified fatty acids and an upregulation of liver injury indicators (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total protein, globulin) in SCK cows compared with healthy cows. The ELISA assays revealed that SCK cows displayed systemic low-grade inflammation, as demonstrated by increased serum levels of haptoglobin, serum amyloid A, TGF-β, IFN-γ, and IL-1β. Liver biopsies revealed pathological histological alterations, hepatic inflammation, and macrophage polarization status. Oil Red staining indicated steatosis, whereas Sirius red staining demonstrated mild extracellular matrix deposition in the liver of SCK cows. The expression of inflammatory response-related proteins (TLR4, p-NFκB, p-I-κB, NLRP3, and Caspase 1) was elevated in the liver of SCK cows, with the increased mean fluorescence intensity of NFκB further confirming the activation of the inflammatory pathway. Furthermore, the levels of pro-inflammatory factors, TNF-α and IFN-γ, were elevated in the tissue homogenate. Macrophage phenotypic changes in SCK cows were further explored based on the results of liver injury and inflammation. Compared with healthy cows, the protein and mRNA abundance of the macrophage marker CD68 in the liver of SCK cows was higher, along with an increased mean fluorescence intensity of CD68. The SCK cows also exhibited reduced mRNA expression of the Kupffer cell marker CLEC4F and elevated chemokine levels (CXCL1 and CCL2). As evidenced by greater protein and mRNA abundance of macrophage M1 polarization markers (iNOS, IL-1β, CD86, IL-6, IL-12b, and CCL3), higher fluorescence intensity of iNOS and CD86, and an increased number of CD68+/CD86+-positive cells observed via immunofluorescence, the macrophage polarization phenotype in the liver of SCK cows was predominantly M1. In contrast, the protein and mRNA abundances of M2 polarization markers (CD206, IL-10, and Arg1) were lower in SCK cows, accompanied by a reduced fluorescence intensity of CD206 and a lower number of CD68+/CD206+-positive cells. Overall, the present study revealed that the number of macrophages in liver is enhanced during subclinical ketosis and is dominated by pro-inflammatory macrophages (M1 macrophages). This could partly explain the increased risk of steatosis, fibrosis, and inflammatory response processes in these cows.

Recurrent aphthous ulcers significantly impact patients' quality of life due to their painful and recurrent nature, necessitating more effective treatments. This study explores the therapeutic potential of Boswellia to treat recurrent aphthous ulcers by its anti-inflammatory and healing promotion effect in a rat oral ulcer model.

Network pharmacology techniques were employed to elucidate Boswellia's active components and potential targets. Intersecting targets of Boswellia and oral ulcer-related genes were screened for protein-protein interaction network analysis and functional enrichment. An oral ulcer model in rats was used and rats were treated with Boswellia extract. The healing process was monitored by measuring the ulcer area and body weight changes. Histological analysis was performed, and the role of Boswellia in macrophage polarization was investigated through gene expression analysis and protein array tests. The underlying mechanism involving PPARγ activation was also explored.

Network pharmacology analysis revealed Boswellia's interaction with key genes and pathways associated with inflammation and lipid metabolism, such as MAPK3, PPARG, and PTGS2. Boswellia extract significantly accelerated oral ulcer healing and recovered weight loss in rats. Histological examinations revealed reduced tissue swelling and inflammatory cell infiltration in treated groups. Furthermore, Boswellia extract decreased infiltration of M1 macrophage presence while increasing M2 macrophage, indicating an inflammation-resolving effect. In vitro studies showed that Boswellia extract enhanced M2-related gene expression and decreased pro-inflammatory cytokines, which is PPARγ dependent.

Boswellia extract promotes oral ulcer healing and resolves inflammation, primarily through the modulation of macrophage polarization via PPARγ activation.

The coagulation and immune system, both essential physiological systems in the human body, are intricately interconnected and play a critical role in determining the overall health of patients. These systems collaborate via various shared regulatory pathways, such as the Tissue Factor (TF) Pathway. Immunological cells that express TF and generate pro-inflammatory cytokines have the ability to affect coagulation. Conversely, coagulation factors and processes have a reciprocal effect on immunological responses by stimulating immune cells and regulating their functions. These interconnected pathways play a role in both preserving well-being and contributing to a range of pathological disorders. The close relationship between blood clotting and inflammation in the development of vascular disease has become a central focus of clinical study. This research specifically examines the crucial elements of this interaction within the contexts of cardiovascular disease and acute coronary syndrome. Tissue factor, the primary trigger of the extrinsic coagulation pathway, has a crucial function by inducing a proinflammatory reaction through the activation of coagulation factors. This, in turn, initiates coagulation and subsequent cellular signalling pathways. Protease-activated receptors establish the molecular connection between coagulation and inflammation by interacting with activated clotting factors II, X, and VII. Thrombosis, a condition characterised by the formation of blood clots, is the most dreaded consequence of cardiovascular disorders and a leading cause of death globally. Consequently, it poses a significant challenge to healthcare systems. Antithrombotic treatments efficiently target platelets and the coagulation cascade, but they come with the inherent danger of causing bleeding. Furthermore, antithrombotics are unable to fully eliminate thrombotic events, highlighting a treatment deficiency caused by a third mechanism that has not yet been sufficiently addressed, namely inflammation. Understanding these connections may aid in the development of novel approaches to mitigate the harmful mutual exacerbation of inflammation and coagulation. Gaining a comprehensive understanding of the intricate interaction among these systems is crucial for the management of diseases and the creation of efficacious remedies. Through the examination of these prevalent regulatory systems, we can discover novel therapeutic approaches that specifically target these complex illnesses. This paper provides a thorough examination of the reciprocal relationship between the coagulation and immune systems, emphasising its importance in maintaining health and understanding disease processes. This review examines the interplay between inflammation and thrombosis and its role in the development of thrombotic disorders.

Knee osteoarthritis (KOA) is a degenerative joint disease characterized by the progressive deterioration of cartilage and synovial inflammation. A critical mechanism in the pathogenesis of KOA is impaired efferocytosis in synovial tissue. The present study aimed to identify and validate key efferocytosis-related genes (EFRGs) in KOA synovial tissue by using comprehensive bioinformatics and machine learning approaches.

We integrated three datasets (GSE55235, GSE55457, and GSE12021) from the Gene Expression Omnibus database to screen differentially expressed genes (DEGs) associated with efferocytosis and performed weighted gene co-expression network analysis. Subsequently, we utilized univariate logistic regression analysis, least absolute shrinkage and selection operator regression, support vector machine, and random forest algorithms to further refine these genes. The results were then inputted into multivariate logistic regression analysis to construct a diagnostic nomogram. Public datasets and quantitative real-time PCR experiments were employed for validation. Additionally, immune infiltration analysis was conducted with CIBERSORT using the combined datasets.

Analysis of the intersection between DEGs and EFRGs identified 12 KOA-related efferocytosis DEGs. Further refinement through machine learning algorithms and multivariate logistic regression revealed UCP2, CX3CR1, and CEBPB as hub genes. Immune infiltration analysis demonstrated significant correlations between immune cell components and the expression levels of these hub genes. Validation using independent datasets and experimental approaches confirmed the robustness of these findings.

This study successfully identified three hub genes (UCP2, CX3CR1, and CEBPB) with significant expression alterations in KOA, demonstrating high diagnostic potential and close associations with impaired efferocytosis. These targets may modulate synovial efferocytosis-related immune processes, offering novel therapeutic avenues for KOA intervention.

Ligamentum flavum hypertrophy (LFH) is a primary contributor to lumbar spinal stenosis. However, a thorough understanding of the cellular and molecular mechanisms driving LFH fibrotic progression remains incomplete.

Single-cell RNA sequencing (scRNA-seq) was performed to construct the single-cell map of human ligamentum flavum (LF) samples. An integrated multi-omics approach, encompassing scRNA-seq, bulk RNA sequencing (bulk RNA-seq), and Mendelian randomization (MR), was applied to conduct comprehensive functional analysis. Clinical tissue specimens and animal models were employed to further confirm the multi-omics findings.

ScRNA-seq provided a single-cell level view of the fibrotic microenvironment in LF, revealing significantly increased proportions of fibroblasts, myofibroblasts, and macrophages in LFH. Using transmission electron microscopy, single-cell gene set scoring, and MR analysis, ferroptosis was identified as a critical risk factor and pathway within LFH. Subcluster analysis of fibroblasts revealed functional heterogeneity among distinct subpopulations, highlighting the functional characteristics and the metabolic dynamics of fibroblast with a high ferroptosis score (High Ferro-score FB). The quantification of gene expression at single-cell level revealed that ferroptosis increased along with fibrosis in LFH specimens, a finding further validated in both human and mice tissue sections. Consistently, bulk RNA-seq confirmed increased proportions of fibroblasts and macrophages in LFH specimens, underscoring a strong correlation between these cell types through Spearman correlation analysis. Notably, subcluster analysis of the mononuclear phagocytes identified a specific subset of SPP1+ macrophages (SPP1+ Mac) enriched in LFH, which exhibited activation of fibrosis and ferroptosis-related metabolic pathways. Cell-cell communication analysis highlighted that SPP1+ Mac exhibited the strongest outgoing and incoming interactions among mononuclear phagocytes in the LFH microenvironment. Ligand-receptor analysis further revealed that the SPP1-CD44 axis could serve as a key mediator regulating the activity of High Ferro-score FB. Multiplex immunofluorescence confirmed substantial Collagen I deposition and reduced Ferritin Light Chain expression in regions with SPP1-CD44 co-localization in LFH specimens.

Our findings indicated that SPP1+ Mac may contribute to LFH fibrosis by regulating ferroptosis in High Ferro-score FB through the SPP1-CD44 axis. This study enhances our understanding of the cellular and molecular mechanisms underlying LFH progression, potentially improving early diagnostic strategies and identifying new therapeutic targets.

Interferon-Induced Protein with Tetratricopeptide Repeats 3 (IFIT3) plays a dual role in innate immunity and tumor immunity, functioning as both a viral defense molecule and a regulator of tumor progression. This review explores the mechanisms through which IFIT3 modulates immune responses, including interferon signaling, RIG-I-like receptors, and the NF-κB pathway. IFIT3 facilitates immune evasion and promotes inflammation-mediated tumor growth by regulating immune checkpoints and the tumor microenvironment, its emerging role as a target for cancer immunotherapy opens new avenues for therapeutic strategies. Finally, this paper underscores IFIT3's potential clinical applications in the modulation of tumor immunity, highlighting the need for further research on IFIT3-targeted therapies.

Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hucMSC-sEV) have recently garnered attention as a potential therapeutic approach for kidney diseases with anti-inflammatory effects. Infiltrated macrophages play an important role in facilitating tissue regeneration. However, the intricate regulatory effects of hucMSC-sEV on macrophages during cisplatin-induced acute kidney injury (AKI) remain unknown. In this study, we uncovered that hucMSC-sEV exhibited potent anti-inflammation and effectively inhibited the polarization of M1 phenotype macrophages. Mechanically, miRNA sequencing analysis and qRT-PCR indicated that a novel miRNA, named miR-13896, was enriched in hucMSC-sEV. When transfected with miR-13896 mimic, macrophages displayed M2 phenotype with elevated levels of Arg1 and IL-10, while miR-13896 inhibitor promoted M1 phenotype. Furthermore, we firstly established that miR-13896 repressed Tradd expression by targeting its 3' untranslated region and subsequently inhibited NF-κB signaling pathway in macrophages. Additionally, to improve therapeutic effects, hucMSC-sEV were engineered with elevated levels of miR-13896 through electroporation, which resulted in promoting M2 phenotype macrophages, inhibiting inflammatory factors, and enhancing kidney repair. Conclusively, our findings provide novel insights into the mechanisms underlying the effects of hucMSC-sEV on macrophages and AKI, while also highlighting electroporation as a promising strategy for treating cisplatin-induced AKI.

M2 macrophage-derived extracellular vesicles (M2-EVs) demonstrate the capacity to reduce pro-inflammatory M1 macrophage formation, thereby restoring the M1-M2 macrophage balance and promoting immunoregulation. However, the efficacy of M2-EVs in regulating macrophage polarization and subsequently enhancing osseointegration around titanium (Ti) implants in patients with diabetes mellitus (DM) remains to be elucidated. In this study, Ti implants were coated with polydopamine to facilitate M2-EVs adherence. In vitro experiment results demonstrated that M2-EVs could carry miR-23a-3p, inhibiting NOD-like receptor protein3(NLRP3) inflammasome activation in M1 macrophage and reducing the levels of inflammatory cytokines such as IL-1β by targeting NEK7. This improved the M1-M2 macrophage balance and enhanced mineralization on the Ti implant surfaces. The in vivo experiment results demonstrated that in diabetic conditions, the nanocoated M2-EVs significantly promoted high-quality bone deposition around the Ti implants. The current results provide a novel perspective for simple and effective decoration of M2-EVs on Ti implants; clinically, the method may afford osteoimmunomodulatory effects enhancing implant osseointegration in patients with DM.

Cardiovascular fibrosis is a common pathological process that contributes to the development and progression of various cardiovascular diseases. Despite being widely believed to be an irreversible and relentless process, preclinical models and clinical trials have shown that cardiovascular fibrosis is an extremely dynamic process. Additionally, as part of the innate immune system, macrophages are heterogeneous cells that are pivotal in tissue regeneration and fibrosis. They participate in fibroblast activation, extracellular matrix remodelling, and the regression of fibrosis. Although we have made some advances in understanding macrophages in cardiovascular fibrosis, a gap still remains between their identification and conversion into effective treatments. Moreover, the traditional M1-M2 paradigm faces many challenges because it does not sufficiently clarify macrophage diversity and their functions. Exploring novel macrophage-based therapies is urgent for cardiovascular fibrosis treatment. Single-cell techniques have shed light on identifying novel subpopulations that differ in function and molecular signature under steady-state and pathological conditions. In this review, we outline the developmental origins of macrophages, which underlie their functions; and recent technology development in the single-cell era. In addition, we describe the markers and mediators of the newly defined macrophage subpopulations and the molecular mechanisms involved to elucidate potential approaches for targeting macrophages in cardiovascular fibrosis.

SMEPPI is a small molecule synthesized as a derivative of KR-62980 that has anti-diabetic and anti-inflammatory activities. Despite the established physiological effects of KR-62980, the effects and benefits of SMEPPI remain largely unexplored. This study investigated the immunomodulatory functions of SMEPPI on macrophages and inflammatory diseases. SMEPPI did not affect the differentiation and maturation of bone marrow-derived monocytes into macrophages, nor did it affect the proliferation of M1 or M2 macrophages. Although SMEPPI did not affect M2 macrophage polarization, it significantly inhibited IL-1β and IL-6 cytokine production in both M1 macrophages and activated RAW264.7 macrophages. Importantly, SMEPPI inhibited the expression and phosphorylation of NF-κB p65 through inhibition of Akt expression, preventing its translocation to the nucleus. It also promoted p65 degradation through the stimulation of the proteasomal degradation pathway by inducing the expression of proteasome-related genes, thereby inhibiting p65 transcriptional activity. SMEPPI also enhanced the expression of various molecules associated with macrophage phagocytosis, including CD68, CD33, and lectins, thereby increasing phagocytic activity. Moreover, SMEPPI mitigated lipopolysaccharides-induced acute lung injury by suppressing IL-1β and IL-6 production in M1 macrophages and reduced mortality related to severe lung injury. These findings indicate that SMEPPI effectively regulates inflammatory diseases by impeding p65-induced cytokine production and enhancement of phagocytosis by M1 macrophages.

Lung cancer is among the most common and deadliest malignant tumors worldwide. It is often detected at late stages, resulting in unfavorable outcomes, with tumor cell heterogeneity and medication resistance. Tumor-associated macrophages are among the key cells contributing to cancer progression. They are categorized into two primary phenotypes: Proinflammatory (M1) and anti-inflammatory (M2) which are involved in the onset and progression of NSCLC. The role of common cytokines secreted by macrophages in the progression of lung cancer are described, and the effects of various substances such as RNA or protein on the differentiation and polarization of two phenotypes of macrophages are highlighted to characterize the impact of the immune state of tumors on therapeutic effect of treatments and patient prognosis. Researchers have primarily aimed to investigate innovative carriers and strategies based on macrophages to modify the tumor microenvironment.

These approaches are often integrated with other treatments, particularly immunotherapy, to enhance therapeutic efficacy.

A comprehensive review was carried out by systematically synthesizing existing literature on PubMed, using the combination of the keywords "TAMs", "NSCLC", "Drug resistance", and "therapy". The available studies were screened for selection based on quality and relevance.

TAMs promote tumor invasion, growth, and metastasis by promoting angiogenesis and EMT. In addition, they contribute to the development of drug resistance and the immunosuppressive microenvironment establishment. The immunosuppressive factors secreted by TAM can weaken the activity of immune cells, inhibit their killing effect on tumors, leading to immune suppression and hindering the effectiveness of treatment. Therefore, TAM is a key target for the development of cancer immunotherapy. Various strategies are being explored, including reducing the recruitment of TAMs and influencing their polarization to treat NSCLC. In addition, TAMs based treatment systems can achieve precise delivery of drugs or gene interfering molecules without causing side effects.