Macrophages are the most abundant immune cells within the synovial joints, and also the main innate immune effector cells triggering the initial inflammatory responses in the pathological process of osteoarthritis (OA). The transition of synovial macrophages between pro-inflammatory and anti-inflammatory phenotypes can play a key role in building the intra-articular microenvironment. The pro-inflammatory cascade induced by TNF-α, IL-1β, and IL-6 is closely related to M1 macrophages, resulting in the production of pro-chondrolytic mediators. However, IL-10, IL1RA, CCL-18, IGF, and TGF are closely related to M2 macrophages, leading to the protection of cartilage and the promoted regeneration. The inhibition of NF-κB signaling pathway is central in OA treatment via controlling inflammatory responses in macrophages, while the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway appears not to attract widespread attention in the field. Nrf2 is a transcription factor encoding a large number of antioxidant enzymes. The activation of Nrf2 can have antioxidant and anti-inflammatory effects, which can also have complex crosstalk with NF-κB signaling pathway. The activation of Nrf2 can inhibit the M1 polarization and promote the M2 polarization through potential signaling transductions including TGF-β/SMAD, TLR/NF-κB, and JAK/STAT signaling pathways, with the regulation or cooperation of Notch, NLRP3, PI3K/Akt, and MAPK signaling. And the expression of heme oxygenase-1 (HO-1) and the negative regulation of Nrf2 for NF-κB can be the main mechanisms for promotion. Furthermore, the candidates of OA treatment by activating Nrf2 to promote M2 phenotype macrophages in OA are also reviewed in this work, such as itaconate and fumarate derivatives, curcumin, quercetin, melatonin, mesenchymal stem cells, and low-intensity pulsed ultrasound.

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Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis

Macrophages are influential members of the innate immune system that can be reversibly polarized by different microenvironment signals. Cell polarization leads to a wide range of features, involving the migration, development, and organization of the cells. There is mounting evidence that macrophage polarization plays a key role in the initiation and development of a wide range of diseases. This study aims to give an overview of macrophage polarization, their different subtypes, and the importance of alternatively activated M2 macrophage and classically activated M1 macrophage in immune responses and pathological conditions. This review provides insight on the role of exosomes in M1/M2-like macrophage polarization and their potential as a promising therapeutic candidate. 

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The role of macrophage subtypes and exosomes in immunomodulation

In this study, we aimed to reveal the resistance mechanism of hepatocellular carcinoma (HCC) cells to sorafenib by exploring the effect of FNDC5 on sorafenib-induced ferroptosis in HCC cells. We compared the expression level of FNDC5 between sorafenib-resistant and sorafenib-sensitive HCC cell lines and the level of ferroptosis between the groups after treatment with sorafenib. We knocked down FNDC5 in drug-resistant cell lines and overexpressed it in sorafenib-sensitive HCC cell lines to further demonstrate the role of FNDC5 in sorafenib-induced ferroptosis. Using PI3K inhibitors, we revealed the specific mechanism by which FNDC5 functions. In addition, we verified our findings obtained in in vitro experiments using a subcutaneous tumorigenic nude mouse model. The findings revealed that FNDC5 inhibits sorafenib-induced ferroptosis in HCC cells. In addition, FNDC5 activated the PI3K/Akt pathway, which in turn promoted the nuclear translocation of Nrf2 and increased the intracellular antioxidant response, thereby conferring resistance to ferroptosis. Our study provides novel insights for improving the efficacy of sorafenib.

FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells

ABSTRACT Human induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) have been believed to be a promising alternative for the stem cell transplantation therapy. The exosomes (Exo) from iMSCs play an important role in several kinds of life activities. The role of exosomes from iMSCs in severe acute pancreatitis (SAP) induced myocardial injury (MI) has not been investigated. The Exo were isolated from iMSCs through differential centrifugation method. The SAP rat model was established with 5% sodium taurocholate injection into the distal end of the bilepancreatic duct. RT-PCR and western blotting were used to measure related gene expression. Masson trichrome and Sirius Red stainings were used to evaluate MI injury. Cardiac function was detected through cardiac ultrasound.Exo promoted cell viability through activating Akt/nuclear factor E2 related factors 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway in vitro. Exo improved MI induced by SAP through activating Akt/Nrf2/HO-1 signaling pathway. Exo improved cardiac function, and suppressed oxidative status in the SAP model. Exo increased the expression of von Willebrand Factor (vWF) and vascular endothelial growth factor (VEGF) through activating Nrf2/HO-1 signaling pathway. Our data indicated that the Exo from iMSCs could improve MI caused by SAP through activating Nrf2/HO-1 axis. These findings firstly unfold the potential application of Exo from iMSCs in treating MI induced by SAP. Abbreviations: LVEF: Left ventricular ejection fraction; LVFS: left ventricular fractional shorten; LVDd: left ventricular end-diastolic diameter; LVDs: left ventricular end-systolic diameter; MI: Myocardial infarction; MSCs: Mesenchymal stem cells; iPSCs: Human-induced pluripotent stem cells; SAP: Severe acute pancreatitis; iMSCs: iPSCs derived VEGF: MSCs; vascular endothelial growth factor; Nrf2: Nuclear factor erythroid 2-related factor; RT-PCR: Real-time polymerase chain reaction; HE: Hematoxylin-eosin; MODS: Multiple organ dysfunction syndrome; PI3K: Phosphatidylinositol 3-kinase; SOD: Superoxide dismutase; FBS: Fetal bovine serum; ECL: Enhanced chemiluminescence; IHC: Immunohistochemistry.

Exosomes from human induced pluripotent stem cells derived mesenchymal stem cells improved myocardial injury caused by severe acute pancreatitis through activating Akt/Nrf2/HO-1 axis

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common condition with high mortality. ALI/ARDS is caused by multiple etiologies, and the main clinical manifestations are progressive dyspnea and intractable hypoxemia. Currently, supportive therapy is the main ALI/ARDS treatment, and there remains a lack of targeted and effective therapeutic strategies. Macrophages are important components of innate immunity. M1 macrophages are pro-inflammatory, while M2 macrophages are anti-inflammatory and promote tissue repair. Mesenchymal stem cells (MSCs) are stem cells with broad application prospects in tissue regeneration due to their multi-directional differentiation potential along with their anti-inflammatory and paracrine properties. MSCs can regulate the balance of M1/M2 macrophage polarization to improve the prognosis of ALI/ARDS. In this paper, we review the mechanisms by which MSCs regulate macrophage polarization and the signaling pathways associated with polarization. This review is expected to provide new targets for the treatment of ALI/ARDS.

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Advances in the Regulation of Macrophage Polarization by Mesenchymal Stem Cells and Implications for ALI/ARDS Treatment

Background Exosomes are considered a substitute for stem cell-based therapy for myocardial infarction (MI). FNDC5, a transmembrane protein located in the cytoplasm, plays a crucial role in inflammation diseases and MI repair. Furthermore, our previous study found that FNDC5 pre-conditioning bone marrow-derived mesenchymal stem cells (BMMSCs) could secrete more exosomes, but little was known on MI repair. Methods Exosomes isolated from BMMSCs with or without FNDC5-OV were injected into infarcted hearts. Then, cardiomyocytes apoptosis and inflammation responses were detected. Furthermore, exosomes were administrated to RAW264.7 macrophage with LPS treatment to investigate its effect on inflammation and macrophage polarization. Results Compared with MSCs-Exo, FNDC5-MSCs-Exo had superior therapeutic effects on anti-inflammation and anti-apoptosis, as well as polarizing M2 macrophage in vivo. Meanwhile, the in vitro results also showed that FNDC5-MSCs-Exo decreased pro-inflammatory secretion and increased anti-inflammatory secretion under LPS stimulation, which partly depressed NF-κB signaling pathway and upregulated Nrf2/HO-1 Axis. Conclusions FNDC5-BMMSCs-derived exosomes play anti-inflammation effects and promote M2 macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis, which may develop a promising cell-free therapy for MI.

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Exosomes secreted by FNDC5-BMMSCs protect myocardial infarction by anti-inflammation and macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 axis.

Lina Shan

Papers

Exosomes secreted by FNDC5-BMMSCs protect myocardial infarction by anti-inflammation and macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 axis.

β-arrestin1 inhibits hypoxic injury-induced autophagy in human pulmonary artery endothelial cells via the Akt/mTOR signaling pathway.