Autophagy deficiency promotes M1 macrophage polarization to exacerbate acute liver injury via ATG5 repression during aging.
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ABSTRACT:
SUBMITTER: Liu R
PROVIDER: S-EPMC8688512 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Necrotizing enterocolitis (NEC) is a life-threatening inflammatory disease in newborns, but the mechanisms remain unclear. Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage function and is essential for proinflammatory M1 macrophage polarization. Our previous data indicated that M1 macrophages promote NEC injury. Here, we investigated whether IRF5 is involved in the pathogenesis of NEC. First, we found that IRF5 was upregulated in infiltrated macrophages in human neonates with NEC compared to controls. We further confirmed IRF5 upregulation in macrophages in experimental murine NEC and that the infiltrated macrophages were predominantly polarized into the M1 but not the M2 phenotype. Myeloid-specific deficiency of Irf5, which was associated with reduced M1 macrophage polarization and systematic inflammation, dramatically prevented experimental NEC. Moreover, we found that the ablation of Irf5 in myeloid cells markedly suppressed intestinal epithelial cell apoptosis and further prevented intestinal barrier dysfunction in experimental NEC. Bioinformatic and chromatin immunoprecipitation analysis further showed that IRF5 binds to the promoters of the M1 macrophage-associated genes Ccl4, Ccl5, Tnf, and Il12b. Overall, our study provides evidence that IRF5 participates in the pathogenesis of NEC, while the deletion of Irf5 in myeloid cells prevents NEC via inhibiting M1 macrophage polarization.
| S-EPMC7746522 | biostudies-literature
Project description:Liver-resident macrophages (Kupffer cells, KCs) and autophagy play critical roles in the pathogenesis of toxin-induced liver injury. Recent evidence indicates that autophagy can regulate macrophage M1/M2 polarization under different inflammatory conditions. Polyamines, including putrescine, spermidine, and spermine (SPM), are polycations with anti-oxidative, anti-aging, and cell autophagy induction properties. This study aimed to determine the mechanisms by which SPM protects against thioacetamide (TAA)-induced acute liver injury in a mouse model. Pretreatment with SPM significantly alleviated liver injury and reduced intrahepatic inflammation in TAA-induced liver injury compared to controls. SPM markedly inhibited M1 polarization, but promoted M2 polarization of KCs obtained from TAA-exposed livers, as evidenced by decreased IL-1β and iNOS gene induction but increased Arg-1 and Mrc-1 gene induction accompanied by decreased STAT1 activation and increased STAT6 activation. Furthermore, pretreatment with SPM enhanced autophagy, as revealed by increased LC3B-II levels, decreased p62 protein expression, and increased ATG5 protein expression in TAA-treated KCs. Knockdown of ATG5 in SPM-pretreated KCs by siRNA resulted in a significant increase in pro-inflammatory TNF-α and IL-6 secretion and decreased anti-inflammatory IL-10 secretion after TAA treatment, while no significant changes were observed in cytokine production in the TAA treatment alone. Additionally, the effect of SPM on regulation of KC M1/M2 polarization was abolished by ATG5 knockdown in TAA-exposed KCs. Finally, in vivo ATG5 knockdown in KCs abrogated the protective effect of SPM against TAA-induced acute liver injury. Our results indicate that SPM-mediated autophagy inhibits M1 polarization, while promoting M2 polarization of KCs in TAA-treated livers via upregulation of ATG5 expression, leading to attenuated liver injury. This study provides a novel target for the prevention of acute liver injury.
| S-EPMC5940752 | biostudies-literature
Project description:Autophagy, a lysosomal degradation pathway, serves as a protective cellular mechanism in maintaining cell and tissue homeostasis under mechanical stimulation. As the mechanosensitive cells, periodontal ligament stem cells (PDLSCs) play an important role in the force-induced inflammatory bone remodeling and tooth movement process. However, whether and how autophagy in PDLSCs influences the inflammatory bone remodeling process under mechanical force stimuli is still unknown. In this study, we found that mechanical force stimuli increased the expression of the autophagy protein LC3, the number of M1 macrophages and osteoclasts, as well as the ratio of M1/M2 macrophages in the compression side of the periodontal ligament in vivo. These biological changes induced by mechanical force were repressed by the application of an autophagy inhibitor 3-methyladenine. Moreover, autophagy was activated in the force-loaded PDLSCs, and force-stimulated PDLSC autophagy further induced M1 macrophage polarization in vitro. The macrophage polarization could be partially blocked by the administration of autophagy inhibitor 3-methyladenine or enhanced by the administration of autophagy activator rapamycin in PDLSCs. Mechanistically, force-induced PDLSC autophagy promoted M1 macrophage polarization via the inhibition of the AKT signaling pathway. These data suggest a novel mechanism that force-stimulated PDLSC autophagy steers macrophages into the M1 phenotype via the AKT signaling pathway, which contributes to the inflammatory bone remodeling and tooth movement process.
| S-EPMC8187804 | biostudies-literature
Project description:BackgroundThe global prevalence of autoimmune hepatitis (AIH) is increasing due in part to the lack of effective pharmacotherapies. Growing evidence suggests that fibroblast growth factor 4 (FGF4) is crucial for diverse aspects of liver pathophysiology. However, its role in AIH remains unknown. Therefore, we investigated whether FGF4 can regulate M1 macrophage and thereby help treat liver inflammation in AIH.MethodsWe obtained transcriptome-sequencing and clinical data for patients with AIH. Mice were injected with concanavalin A to induce experimental autoimmune hepatitis (EAH). The mechanism of action of FGF4 was examined using macrophage cell lines and bone marrow-derived macrophages.ResultsWe observed higher expression of markers associated with M1 and M2 macrophages in patients with AIH than that in individuals without AIH. EAH mice showed greater M1-macrophage polarization than control mice. The expression of M1-macrophage markers correlated positively with FGF4 expression. The loss of hepatic Fgf4 aggravated hepatic inflammation by increasing the abundance of M1 macrophages. In contrast, the pharmacological administration of FGF4 mitigated hepatic inflammation by reducing M1-macrophage levels. The efficacy of FGF4 treatment was compromised following the in vivo clearance of macrophage populations. Mechanistically, FGF4 treatment activated the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-signal pathway in macrophages, which led to reduced M1 macrophages and hepatic inflammation.ConclusionWe identified FGF4 as a novel M1/M2 macrophage-phenotype regulator that acts through the PI3K-AKT-signaling pathway, suggesting that FGF4 may represent a novel target for treating inflammation in patients with AIH.
| S-EPMC11295337 | biostudies-literature
Project description:Macrophages are divided into two subpopulations: classically activated macrophages (M1) and alternatively activated macrophages (M2). BCG (Bacilli Calmette-GuC)rin) activates disabled naC/ve macrophages to M1 macrophages, which act as inflammatory, microbicidal and tumoricidal cells through cell-cell contact and/or the release of soluble factors. Various transcription factors and signaling pathways are involved in the regulation of macrophage activation and polarization. We discovered that BCG-activated macrophages (BAM) expressed a new molecule, and we named it Novel Macrophage Activated Associated Protein 1 (NMAAP1). The current study found that the overexpression of NMAAP1 in macrophages results in M1 polarization with increased expression levels of M1 genes, such as inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-N1), Interleukin 6 (IL-6), Interleukin 12 (IL-12), Monocyte chemoattractant protein-1 (MCP-1) and Interleukin-1 beta (IL-1N2), and decreased expression of some M2 genes, such as Kruppel-like factor 4 (KLF4) and suppressor of cytokine signaling 1 (SOCS1), but not other M2 genes, including arginase-1 (Arg-1), Interleukin (IL-10), transforming growth factor beta (TGF-N2) and found in inflammatory zone 1 (Fizz1). Moreover, NMAAP1 overexpression in the RAW264.7 cell line increased cytotoxicity against MCA207 tumor cells, which depends on increased inflammatory cytokines rather than cell-cell contact. NMAAP1 also substantially enhanced the phagocytic ability of macrophages, which implies that NMAAP1 promoted macrophage adhesive and clearance activities. Our results indicate that NMAAP1 is an essential molecule that modulates macrophages phenotype and plays an important role in macrophage tumoricidal functions.
| S-EPMC4625070 | biostudies-other
Project description:BACKGROUND:Peripheral nerve injury causes limb muscle/bone atrophy, leading to chronic pain. However, the mechanisms underlying muscle/bone atrophy after peripheral nerve injury remain unknown. It was recently reported that M1 macrophages are the main factors responsible for neurogenic inflammation after peripheral nerve injury. We hypothesized that M1 macrophages are important in muscle/bone atrophy after nerve injury. Therefore, we investigated the influence of M1 macrophages on muscle/bone atrophy after nerve injury in mice to prevent muscle/bone atrophy by suppressing M1 macrophages. METHODS:Hindlimb muscle weight and total bone density were measured in a chronic constriction injury (CCI) mouse model. Immunohistochemical analysis and intravital microscopy were performed to visualize hindlimb muscles/bones, and cells were quantified using flow cytometry. We compared M1 macrophage infiltration into muscles/bones and muscle/bone atrophy between macrophage depletion and untreated groups. We also investigated muscle/bone atrophy using administration models for anti-inflammatory and neuropathic pain drugs. RESULTS:Peripheral nerve injury caused significant reduction in muscle weight and total bone density at 1 and 3 weeks after CCI, respectively, compared with that in controls. Osteoclast numbers were significantly higher at 1 week after CCI in the CCI group than in the control group. M1 macrophage infiltration into muscles was observed from 2 h after CCI via intravital microscopy and 1 week after CCI, and it was significantly higher 1 week after CCI than in the control group. In the macrophage depletion group, dexamethasone, pregabalin, and loxoprofen groups, M1 macrophage infiltration into muscles/bones was significantly lower and muscle weight and total bone density were significantly higher than in the untreated group. CONCLUSIONS:M1 macrophage infiltration exacerbates muscle/bone atrophy after peripheral nerve injury. By suppressing M1 macrophages at the neural injury local site, muscle/bone atrophy could be avoided.
| S-EPMC6971979 | biostudies-literature
Project description:Exhaustive exercise (EE) induced hepatic inflammatory injury has been well reported. Dihydromyricetin (DHM) has shown anti-inflammatory bioactivity and hepatoprotective effects but is limited by poor bioavailability. Here, high-bioavailability DHM-encapsulated liposomes were synthesized and explored for their therapeutic potential and regulatory mechanisms in a hepatic inflammatory injury model. The animal model was established by swimming-to-exhaustive exercise in C57BL/6 mice, and the anti-inflammatory effects were detected after administration of DHM or DHM liposome. NIR fluorescence imaging was used to assess the potential of liver targeting. The DHM liposome-induced macrophage polarization was measured by flow cytometry ex vivo. The anti-inflammatory mechanism of DHM was studied in cell line RAW264.7 in vitro. Liposome encapsulation enhanced DHM bioavailability, and DHM liposome could alleviate liver inflammation more effectively. Moreover, DHM liposome targeted hepatic macrophages and polarized macrophages into an anti-inflammatory phenotype. The SIRT3/HIF-1α signaling pathway could be the major mechanism of DHM motivated macrophage polarization. Our study indicates that DHM liposomes can alleviate liver inflammation induced by EE through sustained releasing and hepatic targeting. It is a promising option to achieve the high bioavailability of DHM. Also, this study provides new insights into the regional immune effect of DHM against inflammation.
| S-EPMC9205249 | biostudies-literature
Project description:BackgroundGlioblastoma (GB) is the most common and highly malignant brain tumor characterized by aggressive growth and resistance to alkylating chemotherapy. Autophagy induction is one of the hallmark effects of anti-GB therapies with temozolomide (TMZ). However, the non-classical form of autophagy, autophagy-based unconventional secretion, also called secretory autophagy and its role in regulating the sensitivity of GB to TMZ remains unclear. There is an urgent need to illuminate the mechanism and to develop novel therapeutic targets for GB.MethodsCancer genome databases and paired-GB patient samples with or without TMZ treatment were used to assess the relationship between HMGB1 mRNA levels and overall patient survival. The relationship between HMGB1 protein level and TMZ sensitivity was measured by immunohistochemistry, ELISA, Western blot and qRT-PCR. GB cells were engineered to express a chimeric autophagic flux reporter protein consisting of mCherry, GFP and LC3B. The role of secretory autophagy in tumor microenvironment (TME) was analyzed by intracranial implantation of GL261 cells. Coimmunoprecipitation (Co-IP) and Western blotting were performed to test the RAGE-NFκB-NLRP3 inflammasome pathway.ResultsThe exocytosis of HMGB1 induced by TMZ in GB is dependent on the secretory autophagy. HMGB1 contributed to M1-like polarization of tumor associated macrophages (TAMs) and enhanced the sensitivity of GB cells to TMZ. Mechanistically, RAGE acted as a receptor for HMGB1 in TAMs and through RAGE-NFκB-NLRP3 inflammasome pathway, HMGB1 enhanced M1-like polarization of TAMs. Clinically, the elevated level of HMGB1 in sera may serve as a beneficial therapeutic-predictor for GB patients under TMZ treatment.ConclusionsWe demonstrated that enhanced secretory autophagy in GB facilitates M1-like polarization of TAMs to enhance TMZ sensitivity of GB cells. HMGB1 acts as a key regulator in the crosstalk between GB cells and tumor-suppressive M1-like TAMs in GB microenvironment and may be considered as an adjuvant for the chemotherapeutic agent TMZ.
| S-EPMC8862393 | biostudies-literature
Project description:Calcium oxalate (CaOx) crystal can trigger kidney injury, which contributes to the pathogenesis of nephrocalcinosis. The phenotypes of infiltrating macrophage may impact CaOx-mediated kidney inflammatory injury as well as crystal deposition. How aryl hydrocarbon receptor (AhR) regulates inflammation and macrophage polarization is well understood; however, how it modulates CaOx nephrocalcinosis remains unclear. Methods: Mice were intraperitoneally injected with glyoxylate to establish CaOx nephrocalcinosis model with or without the treatment of AhR activator 6-formylindolo(3,2-b)carbazole (FICZ). Positron emission tomography computed tomography (PET-CT) imaging, Periodic acid-Schiff (PAS) staining, and polarized light optical microscopy were used to evaluate kidney injury and crystal deposition in mice kidney. Western blotting, immunofluorescence, chromatin immunoprecipitation, microRNA-fluorescence in situ hybridization, and luciferase reporter assays were applied to analyze polarization state and regulation mechanism of macrophage. Results: AhR expression was significantly upregulated and negatively correlated with interferon-regulatory factor 1 (IRF1) and hypoxia inducible factor 1-alpha (HIF-1α) levels in a murine CaOx nephrocalcinosis model following administration of FICZ. Moreover, AhR activation suppressed IRF1 and HIF-1α levels and decreased M1 macrophage polarization in vitro. In terms of the mechanism, bioinformatics analysis and chromatin immunoprecipitation assay confirmed that AhR could bind to miR-142a promoter to transcriptionally activate miR-142a. In addition, luciferase reporter assays validated that miR-142a inhibited IRF1 and HIF-1α expression by directly targeting their 3'-untranslated regions. Conclusions: Our results indicated that AhR activation could diminish M1 macrophage polarization and promote M2 macrophage polarization to suppress CaOx nephrocalcinosis via the AhR-miR-142a-IRF1/HIF-1α pathway.
| S-EPMC7667681 | biostudies-literature
Project description:Macrophages are key participants in melanoma growth and survival. In general, macrophages can be classified as M1 or M2 activation phenotypes. Increasing evidence demonstrates that melanoma exosomes also facilitate tumor survival and metastasis. However, the role of melanoma exosomes in directly influencing macrophage function is poorly understood. Herein, we investigated the hypothesis that natural melanoma exosomes might directly influence macrophage polarization. To explore this hypothesis, ELISA, RT-qPCR, and macrophage functional studies were performed in vitro using an established source of melanoma exosomes (B16-F10). ELISA results for melanoma exosome induction of common M1 and M2 cytokines in RAW 264.7 macrophages, revealed that melanoma exosomes do not polarize macrophages exclusively in the M1 or M2 direction. Melanoma exosomes induced the M1 and M2 representative cytokines TNF-? and IL-10 respectively. Further assessment, using an RT-qPCR array with RAW 264.7 and primary macrophages, confirmed and extended the ELISA findings. Upregulation of markers common to both M1 and M2 polarization phenotypes included CCL22, IL-12B, IL-1?, IL-6, i-NOS, and TNF-?. The M2 cytokine TGF-? was upregulated in primary but not RAW 264.7 macrophages. Pro-tumor functions have been attributed to each of these markers. Macrophage functional assays demonstrated a trend toward increased i-NOS (M1) to arginase (M2) activity. Collectively, the results provide the first evidence that melanoma exosomes can induce a mixed M1 and M2 pro-tumor macrophage activation phenotype.
| S-EPMC5857255 | biostudies-literature