Anti-inflammatory Phenotype Research Articles

Therapeutic Potential of Vanillic Acid in Ulcerative Colitis Through Microbiota and Macrophage Modulation.

This study investigated the protective effects of the dietary polyphenol vanillic acid (VA) on dextran sulfate sodium-induced acute ulcerative colitis (UC) in mice, focusing on its impact on the gut microbiota and inflammatory responses. VA was supplemented following dextran sulfate sodium administration, and key indicators, including body weight, disease activity index, colon length, spleen index, and inflammatory markers, were assessed. VA supplementation significantly alleviated UC symptoms, preserved intestinal barrier integrity, and reduced pro-inflammatory cytokine levels. Additionally, VA positively altered the gut microbiota composition, promoting beneficial bacteria such as Akkermansia muciniphila while suppressing the arachidonic acid metabolism pathway. Fecal microbiota transplantation confirmed that the VA-modified gut microbiota contributed to these protective effects. VA also facilitated macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, further mitigating inflammation. These findings highlight the potential of VA as a natural dietary intervention for UC, emphasizing its role in regulating the gut microbiota and inflammatory pathways, which may have significant nutritional relevance in managing inflammatory bowel diseases.

Traditional Chinese Medicine Borneol-Based Polymeric Micelles Intracerebral Drug Delivery System for Precisely Pathogenesis-Adaptive Treatment of Ischemic Stroke.

The scarcity of effective neuroprotective agents and the presence of blood-brain barrier (BBB)-mediated extremely inefficient intracerebral drug delivery are predominant obstacles to the treatment of cerebral ischemic stroke (CIS). Herein, ROS-responsive borneol-based amphiphilic polymeric NPs are constructed by using traditional Chinese medicine borneol as functional blocks that served as surface brain-targeting ligand, inner hydrophobic core for efficient drug loading of membrane-permeable calcium chelator BAPTA-AM, and neuroprotective structural component. In MCAO mice, the nanoformulation (polymer: 3.2 mg·kg-1, BAPTA-AM: 400 µg·kg-1) reversibly opened the BBB and achieved high brain biodistribution up to 12.7%ID/g of the total administered dose after 3 h post single injection, effectively restoring intracellular Ca2+ and redox homeostasis, improving cerebral histopathology, and inhibiting mitochondrial PI3K/Akt/Bcl-2/Bax/Cyto-C/Caspase-3,9 apoptosis pathway for rescuing dying neurons (reduced apoptosis cell from 59.5% to 7.9%). It also remodeled the inflammatory microenvironment in cerebral ischemic penumbra by inhibiting astrocyte over-activation, reprogramming microglia polarization toward an anti-inflammatory phenotype, and blocking NF-κB/TNF-α/IL-6 signaling pathways. These interventions eventually reduced the cerebral infarction area by 96.3%, significantly improved neurological function, and restored blood flow reperfusion from 66.2% to ≈100%, all while facilitating BBB repair and avoiding brain edema. This provides a potentially effective multiple-stage sequential treatment strategy for clinical CIS.

Clinical-grade extracellular vesicles derived from umbilical cord mesenchymal stromal cells: preclinical development and first-in-human intra-articular validation as therapeutics for knee osteoarthritis

Osteoarthritis (OA) is a joint disease characterized by articular cartilage degradation. Persistent low-grade inflammation defines OA pathogenesis, with crucial involvement of pro-inflammatory M1-like macrophages. While mesenchymal stromal cells (MSC) and their small extracellular vesicles (sEV) hold promise for OA treatment, achieving consistent clinical-grade sEV products remains a significant challenge. This study aims to develop fully characterized, reproducible, clinical-grade batches of sEV derived from umbilical cord (UC)-MSC for the treatment of OA while assessing its efficacy and safety. Initially, a standardized, research-grade manufacturing protocol was established to ensure consistent sEV production. UC-MSC-sEV characterization under non-cGMP conditions showed consistent miRNA and protein profiles, suggesting their potential for standardized manufacturing. In vitro studies evaluated the efficacy, safety, and potency of sEV; animal studies confirmed their effectiveness and safety. In vitro, UC-MSC-sEV polarized macrophages to an anti-inflammatory M2b-like phenotype, through STAT1 modulation, indicating their potential to create an anti-inflammatory environment in the affected joints. In silico studies confirmed sEV's immunosuppressive signature through miRNA and proteome analysis. In an OA mouse model, sEV injected intra-articularly (IA) induced hyaline cartilage regeneration, validated by histological and μCT analyses. The unique detection of sEV signals within the knee joint over time highlights its safety profile by confirming the retention of sEV in the joint. The product development of UC-MSC-sEV involved refining, standardizing, and validating processes in compliance with GMP standards. The initial assessment of the safety of the clinical-grade product via IA administration in a first-in-human study showed no adverse effects after a 12 month follow-up period. These results support the progress of this sEV-based therapy in an early-phase clinical trial, the details of which are presented and discussed in this work. This study provides data on using UC-MSC-sEV as local therapy for OA, highlighting their regenerative and anti-inflammatory properties and safety in preclinical and a proof-of-principle clinical application.Graphical

Resveratrol-driven macrophage polarization: unveiling mechanisms and therapeutic potential

Resveratrol, a polyphenolic compound known for its diverse biological activities, has demonstrated multiple pharmacological effects, including anti-inflammatory, anti-aging, anti-diabetic, anti-cancer, and cardiovascular protective properties. Recent studies suggest that these effects are partly mediated through the regulation of macrophage polarization, wherein macrophages differentiate into pro-inflammatory M1 or anti-inflammatory M2 phenotypes. Our review highlights how resveratrol modulates macrophage polarization through various signaling pathways to achieve therapeutic effects. For example, resveratrol can activate the senescence-associated secretory phenotype (SASP) pathway and inhibit the signal transducer and activator of transcription (STAT3) and sphingosine-1-phosphate (S1P)-YAP signaling axes, promoting M1 polarization or suppressing M2 polarization, thereby inhibiting tumor growth. Conversely, it can promote M2 polarization or suppress M1 polarization by inhibiting the NF-κB signaling pathway or activating the PI3K/Akt and AMP-activated protein kinase (AMPK) pathways, thus alleviating inflammatory responses. Notably, the effect of resveratrol on macrophage polarization is concentration-dependent; moderate concentrations tend to promote M1 polarization, while higher concentrations may favor M2 polarization. This concentration dependence offers new perspectives for clinical treatment but also underscores the necessity for precise dosage control when using resveratrol. In summary, resveratrol exhibits significant potential in regulating macrophage polarization and treating related diseases.

Self-Cascade of ROS/Glucose-Scavenging Immunomodulatory Hydrogels for Programmed Therapeutics of Infected Diabetic Ulcers via Nrf2/NF-κB Pathway.

Diabetic ulcers (DUs) are characterized by a microenvironment with high oxidative stress, high blood glucose levels, and recalcitrant bacterial infections. This microenvironment is accompanied by long-term suppression of endogenous antioxidant systems, which makes their clinical management extremely challenging. To address this issue, a hybridized novel gold-palladium (AuPd) nanoshell of the injectable/injectable hydrogel system UiO/AuPdshells/BNN6/PEG@Gel (UAPsBP@Gel) is developed. The system is capable of acting as a nitric oxide (NO) reactor utilizing synergistic therapy that harnesses NIR-II light-triggered photothermal effects and controlled release of NO gas for synergistic treatment to eradicate biofilm infections at different depths. The AuPd nanoshells exhibits superoxide dismutase (SOD)-, glucose oxidase (GOx)-, and catalase (CAT)-like activities, enabling self-cascade process for scavenging both reactive oxygen species (ROS) and glucose. This activity reshapes the DUs microenvironment, switches on the endogenous antioxidant Nrf2/HO-1 pathway and inhibits the NF-κB pathway, promotes macrophage polarization toward the anti-inflammatory M2 phenotype, and reduces oxidative stress, resulting in efficient immunomodulation. In vitro/in vivo results demonstrate that the UAPsBP@Gel can multifacetedly enhance the epithelial rejuvenation process through wound hemostasis, pro-cellular migration and vascularization. These results highlight that a programmed therapeutic based on UBAPsP@Gel tailored to the different stages of infected DUs can meet complex clinical needs.

Chronic traumatic brain injury induces neurodegeneration, neuroinflammation, and cognitive deficits in a T cell-dependent manner.

Traumatic brain injury (TBI) can lead to chronic neuroinflammation, and neurodegeneration associated with long-term cognitive deficits. Following TBI, the acute neuroinflammatory response involves microglial activation and the release of proinflammatory cytokines and chemokines which induce the recruitment of peripheral immune cells such as monocytes and ultimately T cells. Persistent innate and adaptive immune cells response can lead to chronic neurodegeneration and functional deficits. Therefore, understanding the dynamic interaction between chronic immune responses and TBI-related pathogenesis and progression of the disease is crucial. We hypothesized that T cells have an essential role in TBI severity and recovery. We used generic T cell deletion mice (TCRβ-/-δ-/-) vs Wild-type mice that underwent to controlled cortical impact assessing behavioral, histological, and immune system response outcomes at 3 months post-TBI. The absence of T cells reduced neurodegeneration and was associated with improved neurological outcomes 3 months post-injury. Furthermore, the absence of T cells enhanced an anti-inflammatory phenotype in peripheral myeloid cells in the injured brain. Collectively, these data indicate that T cells promote persistent neuropathology and functional impairments chronically after TBI.

Immunomodulatory effects of calcium phosphate microspheres: influences of particle size on macrophage polarization and secretion patterns.

This study investigated the immunomodulatory effects of calcium phosphate (CaP) microspheres, focusing on how particle size influenced macrophage polarization and cytokine secretion patterns. SEM analysis revealed that HA microspheres predominantly exhibited a spherical shape with distinct sizes and sub-micro-sized pores. The average particle sizes for the S1, S2, and S3 groups were 17.36 μm, 27.59 μm, and 47.14 μm, respectively. In vitro experiments demonstrated that small-sized S1 microspheres were more readily phagocytosed by macrophages, leading to a pro-inflammatory M1 phenotype characterized by increased gene expression of iNos and inflammatory cytokines (IL-1β, IL-6, TNF-α), and a higher proportion of CCR7+ M1 macrophages. In contrast, the larger S2 and S3 microspheres favored an anti-inflammatory M2 phenotype, with higher expression of Arg and anti-inflammatory cytokines (IL-10), and greater proportions of CD206+ M2 macrophages. Additionally, HA microspheres were injected into mouse quadriceps muscles, revealing significant differences in immune cell infiltration and tissue response. The S1 microspheres induced a prolonged and more severe inflammatory response, while the S2 and S3 microspheres were embedded in cell-rich tissue with minimal inflammation or fibrosis. It indicated the potential of larger microspheres (S2 and S3) to create a more favorable immune microenvironment that supported faster and more effective tissue healing. These findings underscore the importance of optimizing microsphere size to achieve desired immunomodulatory effects, thereby enhancing their clinical efficacy.

HCeO2@CA-074Me Nanoparticles Alleviate Inflammation and Improve Osteogenic Microenvironment by Regulating the CTSB-NLRP3 Signaling Pathway.

It is well established that the interaction between osteogenesis and inflammation can impact bone tissue regeneration. The use of nanoparticles to treat and alleviate inflammation at the molecular level has the potential to improve the osteogenic microenvironment and serve as a therapeutic approach. We have synthesized new hollow cerium oxide nanoparticles and doped with cathepsin B inhibitor (CA-074Me) to create novel hCeO2@CA-074Me NPs. We characterized the surface morphology and physicochemical properties of hCeO2@CA-074Me NPs. Macrophage RAW 264.7 was cultured with hCeO2@CA-074Me NPs using P. gingivalis-LPS (P.g-LPS) stimulation as a model of inflammation. RT-PCR and Western blot analysis was employed to evaluate the effects of hCeO2@CA-074Me NPs on macrophage phenotype and the CTSB-NLRP3 signaling pathway. To further investigate the inflammatory osteogenic microenvironment, MC3T3-E1 cells were cultured with P.g-LPS to create an in vitro osteogenic conditions under inflammation. The cells were then co-cultured with hCeO2@CA-074Me NPs for 7, 14, and 21 d. The osteogenic ability was evaluated using ALP staining, ALP quantitative analysis, alizarin red staining, and RT-PCR analysis. Findings clearly demonstrated that hCeO2@CA-074Me NPs could effectively reduce the production of ROS and inhibited CTSB-NLRP3 signal pathway, thereby significantly attenuating the damage caused by the cellular inflammatory response. hCeO2@CA-074Me NPs could also induce the polarization of macrophages towards anti-inflammatory M2 phenotype. Additionally, results confirmed that hCeO2@CA-074Me NPs could inhibit inflammation and ameliorate osteogenic microenvironment, thus promoting the osteogenesis of MC3T3-E1 cells. The synthetic hCeO2@CA-074Me NPs could able to modify the osteogenic microenvironment under inflammatory conditions by simultaneously inhibiting the CTSB-NLRP3 signaling pathway and regulating the macrophage phenotype through their ability to scavenge ROS. Based on these findings, our study may offer a promising approach for managing inflammatory bone damage.

A Disintegrin and Metalloproteinase 17 Disrupts Bovine Macrophage MER Proto-Oncogene Tyrosine Kinase Integrity to Impede Apoptotic Cell Clearance and Promote Inflammation in Clinical Mastitis.

In clinical mastitis of dairy cows, the abnormal accumulation of apoptotic cells (ACs) and subsequent secondary necrosis and inflammation pose significant concerns, with macrophage-mediated efferocytosis, crucial for ACs clearance, remaining unexplored in this context. In nonruminants, MER proto-oncogene tyrosine kinase (MERTK) receptors are essential for efferocytosis and A Disintegrin and Metalloproteinase 17 (ADAM17) is thought to play a role in regulating MERTK integrity. This study aimed to delineate the in situ role of efferocytosis in clinical mastitis, with a particular focus on the interaction between MERTK and ADAM17 in bovine macrophages. In mastitic mammary tissue, a significant accumulation of ACs was observed, along with active macrophage efferocytosis. Western blotting analysis revealed elevated expressions of MERTK and ADAM17, and immunofluorescence confirmed that MERTK is predominantly localized within CD163+ macrophages. Additionally, elevated levels of soluble MERTK (sol-MER) in serum indicated impaired integrity and functionality of MERTK. In vitro experiments with the bovine macrophage cell line Bo-mac cells selectively phagocytosed apoptotic MAC-T cells, a process associated with increased MERTK phosphorylation and an anti-inflammatory phenotype. The activation of ADAM17 by Phorbol 12-myristate 13-acetate (PMA) induced sol-Mer release and impaired efferocytosis, with these effects reversed by the ADAM17 inhibitor TAPI-1. Bo-mac efferocytosis was influenced by the presence and activation of MERTK. Silencing MERTK interrupted efferocytosis, a phenomenon also observed with the inhibition of MERTK phosphorylation by UNC2025, which concurrently suppressed anti-inflammatory cytokine production. These findings suggest that targeting the MERTK-ADAM17 axis could enhance inflammatory resolution, providing a novel therapeutic strategy for dairy cattle health management.

Innovative hydrogel delivery of bone marrow stromal cell-derived exosomes for enhanced bone healing.

Bone regeneration is a multifaceted process involving the well-coordinated interaction of cellular functions such as the regulation of inflammation, the formation of new blood vessels, and the development of bone tissue. Bone regeneration is a multifaceted process involving the well-coordinated interplay of multiple cellular activities, such as inflammation control, blood vessel and bone tissue. Zhang et al developed a multifunctional hydrogel system embedded with bone marrow stromal cell-derived exosomes to address the challenges of large bone defects. This innovative approach demonstrated the dual-role capability of bone marrow stromal cell-derived exosomes in directing cell fate by significantly enhancing both angiogenesis and osteogenic differentiation in vitro. The hydrogel system effectively promoted the polarization of macrophages towards the anti-inflammatory M2 phenotype, fostering an environment that supports bone repair. The effectiveness of this hydrogel was validated in a murine fracture model, which promoted significant bone regeneration and functional vascularization. Despite compelling evidence, this study highlights areas for further investigation, including detailed descriptions of experimental procedures, control group selection, long-term outcomes, and the evaluation of inflammation status in vivo. Addressing these limitations will enhance the robustness and impact of the findings.

Calceolarioside B inhibits SARS-CoV-2 Omicron BA.2 variant cell entry and modulates immune response

This study evaluated the inhibitory effects of calceolarioside B, extracted from the traditional Chinese herb Mutong (Akebia quinata Thumb), on the SARS-CoV-2 Omicron BA.2 variant. Molecular docking and molecular dynamics simulations predicted the binding sites and interactions between calceolarioside B and the Omicron BA.2 spike (S) protein. Biolayer interferometry (BLI) and immunofluorescence assays validated its high-affinity binding. Pseudovirus entry assays assessed the inhibitory effects of calceolarioside B on viral entry into host cells, while enzyme-linked immunosorbent assay (ELISA) measured inflammatory cytokine levels. Flow cytometry was used to analyze its effects on macrophage phenotype switching. Results demonstrated that calceolarioside B could bind to the Omicron BA.2 S protein with high affinity, and significantly inhibited viral entry into host cells by interfering with the binding of angiotensin-converting enzyme 2 (ACE2) receptor and S protein. Additionally, calceolarioside B reduced IL(interleukin)-6 expression levels and promoted the switch of macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. These findings suggest that calceolarioside B possesses antiviral and immunomodulatory effects, making it a potential dual-function inhibitor for the treatment of COVID-19.

Reprogramming Macrophage Phenotypes with Photobiomodulation for Enhanced Inflammation Control in ENT Organ Tissues.

Photobiomodulation (PBM), a noninvasive phototherapy using wavelengths ranging between red and near-infrared light, has emerged as a promising approach for controlling inflammation by modulating macrophage polarization. This review investigates the therapeutic potential of PBM in treating ear, neck, and throat (ENT)-specific inflammatory conditions, such as chronic rhinosinusitis and otitis media, focusing on its effects on macrophage phenotypes and evidence from preclinical studies. By promoting mitochondrial activity, increasing ATP production, and modulating reactive oxygen species, PBM has been shown to shift macrophages from a proinflammatory to an anti-inflammatory phenotype. Studies demonstrate that PBM enhances tissue repair, reduces inflammatory markers, and promotes wound healing. Moreover, PBM facilitates the polarization of M2 macrophages, a crucial factor in resolving mucosal inflammation in the nasal, pharyngeal, and middle ear cavities, and restoring tissue homeostasis. The antiinflammatory effects of PBM are attributed to its ability to influence several molecular mechanisms involved in inflammation regulation, particularly in ENT organ tissues, where recurrent inflammation can lead to chronic conditions such as otitis media or sinusitis. Furthermore, this review compares PBM to competing methods for reprogramming macrophages and treating inflammation, highlighting PBM's advantages of minimal toxicity, simplicity, and precision in controlling ENT immune responses.

Levels of Synovial Fluid Inflammatory Biomarkers on Day of Arthroscopic Partial Meniscectomy Predict Long-Term Outcomes and Conversion to TKA: A 10-Year Mean Follow-up Study.

The purpose of the present study was to evaluate the relationships of the concentrations of pro- and anti-inflammatory biomarkers in the knee synovial fluid at the time of arthroscopic partial meniscectomy (APM) to long-term patient-reported outcomes (PROs) and conversion to total knee arthroplasty (TKA). A database of patients who underwent APM for isolated meniscal injury was analyzed. Synovial fluid had been aspirated from the operatively treated knee prior to the surgical incision, and concentrations of pro- and anti-inflammatory biomarkers (RANTES, IL-6, MCP-1, MIP-1β, VEGF, TIMP-1, TIMP-2, IL-1RA, MMP-3, and bFGF) were quantified. Prior to surgery and again at the time of final follow-up, patients were asked to complete a survey that included a visual analog scale (VAS) for pain and Lysholm, Tegner, and Knee injury and Osteoarthritis Outcome Score-Physical Function Short Form (KOOS-PS) questionnaires. Clustering analysis of the 10 biomarkers of interest was carried out with the k-means algorithm. Of the 82 patients who met the inclusion criteria for the study, 59 had not undergone subsequent ipsilateral TKA or APM, and 43 (73%) of the 59 completed PRO questionnaires at long-term follow-up. The mean follow-up time was 10.6 ± 1.3 years (range, 8.7 to 12.4 years). Higher concentrations of individual pro-inflammatory biomarkers including MCP-1 (β = 13.672, p = 0.017) and MIP-1β (β = -0.385, p = 0.012) were associated with worse VAS pain and Tegner scores, respectively. K-means clustering analysis separated the cohort of 82 patients into 2 groups, one with exclusively higher levels of pro-inflammatory biomarkers than the second group. The "pro-inflammatory phenotype" cohort had a significantly higher VAS pain score (p = 0.024) and significantly lower Lysholm (p = 0.022), KOOS-PS (p = 0.047), and Tegner (p = 0.009) scores at the time of final follow-up compared with the "anti-inflammatory phenotype" cohort. The rate of conversion to TKA was higher in the pro-inflammatory cohort (29.4% versus 12.2%, p = 0.064). Logistic regression analysis demonstrated that the pro-inflammatory phenotype was significantly correlated with conversion to TKA (odds ratio = 7.220, 95% confidence interval = 1.028 to 50.720, p = 0.047). The concentrations of synovial fluid biomarkers on the day of APM can be used to cluster patients into pro- and anti-inflammatory cohorts that are predictive of PROs and conversion to TKA at long-term follow-up. Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Gene-Activating Framework Nucleic Acid-Targeted Upregulating Sirtuin-1 to Modulate Osteoimmune Microenvironment for Diabetic Osteoporosis Therapeutics.

Diabetic osteoporosis, a prevalent chronic complication of diabetes, is marked by reduced bone mass, increased bone fragility, and susceptibility to fractures. A significant cause of this condition is the disruption of osteoblastic homeostasis due to prolonged hyperglycemia, which impedes bone regeneration and remodeling. Despite its prevalence, no effective treatments specifically target diabetic osteoporosis. Recently, small-activating RNA (saRNA) therapy has attracted attention for its targeting capacity, high efficacy, and minimal side effects. However, RNA's inherent properties, such as structural instability, susceptibility to degradation, and poor penetration, limit its applications. To address these limitations, a gene-activating tetrahedral framework nucleic acid (tFNA) with sirtuin-1 (SIRT1) gene activation function is developed, termed Tsa. Tsa exhibits an RNA-protecting effect and can effectively penetrate cell membranes to upregulate SIRT1 gene expression. At the histological level, Tsa treatment alleviates diabetic osteoporosis by increasing bone trabecular density and promoting new bone formation. At the cellular level, it switches macrophage polarization toward the anti-inflammatory M2 phenotype while inhibiting the inflammatory M1 phenotype, creating a favorable bone immune microenvironment for osteoblasts. At the genetic level, Tsa activates SIRT1 expression, which deacetylates Acetyl-p65 to block the NF-κB pathway and restore the osteoimmune environment. Overall, this research demonstrates a nanodrug "Tsa", capable of activating SIRT1 and modulating the bone immune environment, thereby showcasing its immense potential for diabetic osteoporosis treatment.

Injectable microspheres filled with copper-containing bioactive glass improve articular cartilage healing by regulating inflammation and recruiting stem cells

Abstract Osteoarthritis (OA) is a frequent chronic illness in orthopaedics that poses a major hazard to patient health. In situ cell therapy is emerging as a therapeutic option, but its efficacy is influenced by both the inflammatory milieu and the amount of stem cells, limiting its use. In this study, we designed a novel injectable porous microsphere (PM) based on microfluidic technology that can support in situ mesenchymal stem cells (MSCs) therapy by combining polylactic-glycolic acid copolymer, kartogenin, polydopamine, stromal cell-derived factor-1, and copper-doped bioactive glass (CuBG). The ex vivo tests demonstrated that PMs@CuBG microspheres were biocompatible and facilitated the transformation of synovial macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotypes by releasing CuBG to reduce joint inflammation. At the same time, the microspheres are able recruit MSCs into the joint cavity and encourage their differentiation into chondrocytes, thereby treating articular cartilage injury. The in vivo rat experimental results show that intra-articular injection of PMs@CuBG in rats with OA improves OARSI scores, Aggrecan content, and the ratio of Col-2α positive cells, indicating a reparative effect on damaged cartilage within the joint. As a result, PMs@CuBG microspheres are predicted to provide a novel and successful approach to in situ cell therapy for OA.

CD11b deficiency attenuates the ischemia/reperfusion-induced AKI-to-CKD process by regulatingmacrophage polarization.

Severe acute kidney injury (AKI) is a risk factor for the future development of chronic kidney disease (CKD), and macrophages are an essential cell group implicated in injury, repair, and fibrosis during this progress. However, the underlying mechanism of how macrophages participate in the development of the disease is largely unclear. CD11b (Integrin αM) is highly expressed in monocytes/macrophages and has been verified to mediate broad functions. We found that CD11b-knockout mice were protected from the ischemia/reperfusion-induced AKI-to-CKD process. Additionally, renal macrophages from the kidneys of CD11b-deficient mice presented an M2-like, anti-inflammatory phenotype. We demonstrated both invitro and invivo that enhanced alternative activation in CD11b-knockout macrophages is regulated by the interleukin (IL)-4/signal transducer and activator of transcription (STAT) 6 axis, which is mediated by the inactivation of the Src-family kinase (SFK) member Lyn. Importantly, the therapeutical administration of CD11b-neutralizing antibody can effectively prevent AKI-to-CKD progress. Thus, our study verifies that CD11b plays a critical role in limiting the alternative activation of macrophages and may be a potential therapeutic target during the AKI-to-CKD process.

Temporal Tissue Remodeling in Volumetric Muscle Injury with Endothelial Cell-Laden Patterned Nanofibrillar Constructs.

A primary challenge following severe musculoskeletal trauma is incomplete muscle regeneration. Current therapies often fail to heal damaged muscle due to dysregulated healing programs and insufficient revascularization early in the repair process. There is a limited understanding of the temporal changes that occur during the early stages of muscle remodeling in response to engineered therapies. Previous work demonstrated that nanotopographically patterned scaffolds provide cytoskeletal guidance and direct endothelial angiogenic and anti-inflammatory phenotypes. The aim of this study was to evaluate how endothelial cell (EC) patterning guides temporal and histomorphological muscle remodeling after muscle injury. In the current study, mice were treated with EC-laden engineered constructs that exhibited either aligned or random patterning of collagen nanofibrils, following a volumetric muscle loss injury (VML). Remodeling was evaluated at 2, 7, and 21 days post injury. Over the 21-day study, all groups (Acellular Aligned, EC Aligned, EC Random) demonstrated similar significant increases in vascular density and myogenesis. Animals treated with acellular controls demonstrated a two-fold decrease in muscle cross-sectional area between days 2 and 21 post injury, consistent with VML-induced muscle atrophy; however, animals treated with patterned EC-laden constructs exhibited preservation of muscle mass. The implantation of an EC-laden construct led to a 50% increase in the number of animals exhibiting areas of fibrous remodeling adjacent to the construct, along with greater collagen deposition (p < 0.01) compared to acellular controls 21 days post injury. These findings suggest that nanotopographically patterned EC-laden constructs may guide early muscle-protective programs that support muscle mass retention through myo-vascular independent pathways.

ABCG1 orchestrates adipose tissue macrophage plasticity and insulin resistance in obesity by rewiring saturated fatty acid pools.

The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between ABCG1 expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.

HDAC6-Mediated FoxO1 Acetylation And Phosphorylation Control Periodontal Inflammatory Responses.

Post-translational modifications (PTMs) are critical regulators of protein function and cellular signaling. While histone deacetylation by histone deacetylases (HDACs) is well established, the role of specific HDACs in modulating non-histone protein PTMs, particularly in an infectious context, is poorly understood. Here, we reveal a pivotal role for HDAC6 in orchestrating periodontal inflammation through its dual regulatory effects on FoxO1 acetylation and phosphorylation. Using Porphyromonas gingivalis , a key periodontal pathogen, as a model pathogen, we observed that infection induces HDAC6 activation, driving inflammatory responses via modulating FoxO1 activity. HDAC6 depletion increased FoxO1 acetylation and phosphorylation, leading to its cytoplasmic sequestration and subsequent suppression of FoxO1- mediated pro-inflammatory cytokine production in macrophages. Mechanistically, HDAC6 deficiency not only directly enhances the acetylation of FoxO1 but also upregulates the expression of Rictor, a critical component of the mTORC2 complex, thereby promoting Akt phosphorylation and subsequently FoxO1 phosphorylation. This results in its cytoplasmic retention and attenuated inflammatory transcriptional activity. Functional studies demonstrated that HDAC6 depletion suppressed the production of key inflammatory mediators, including TNFα, IL-6, IL-12p40, and MIP-2, while promoting macrophage polarization toward anti-inflammatory M2 phenotypes. In vivo , using oral gavage infection and ligature-induced mouse periodontitis models, HDAC6 deficiency significantly reduced inflammatory cell infiltration in gingival tissues and protected against alveolar bone loss. These findings establish HDAC6 as a central regulator of periodontal inflammation, acting through the coordinated modulation of FoxO1 acetylation and phosphorylation. Beyond its role in oral pathology, HDAC6 may serve as a promising therapeutic target for managing inflammatory diseases linked to immune dysregulation.

From acute lung injury to cerebral ischemia: a unified concept involving intercellular communication through extracellular vesicle-associated miRNAs released by macrophages/microglia.

Ischemic stroke and acute lung injury are prevalent life-threatening conditions marked by intricate molecular mechanisms and elevated mortality rates. Despite evident pathophysiological distinctions, a notable similarity exists in the gene responses to tissue injury observed in both pathologies. This similarity extends to both protein-encoding RNAs and non-coding RNAs. Extracellular vesicles (EVs) are nano-scale vesicles derived through cell secretion, possessing unique advantages such as high biocompatibility, low immunogenicity, intrinsic cell targeting, and facile chemical and genetic manipulation. Importantly, miRNAs, the most prevalent non-coding RNAs, are selectively concentrated within EVs. Macrophages/microglia serve as immune defense and homeostatic cells, deriving from progenitor cells in the bone marrow. They can be classified into two contrasting types: classical proinflammatory M1 phenotype or alternative anti-inflammatory M2 phenotype. However, there exists a continuum of various intermediate phenotypes between M1 and M2, and macrophages/microglia can transition from one phenotype to another. This review will investigate recent discoveries concerning the impact of EVs derived from macrophages/microglia under various states on the progression of ischemic stroke and acute lung injury. The focus will be on the involvement of miRNAs within these vesicles. The concluding remarks of this review will underscore the clinical possibilities linked to EV-miRNAs, accentuating their potential as both biomarkers and therapeutic targets.