Browsing by Subject "Macrophage polarization"

Now showing 1 - 3 of 3
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    Mechanical Loading Mitigates Osteoarthritis Symptoms by Regulating the Inflammatory Microenvironment
    (SSRN, 2021-06-14) Zhang, Weiwei; Li, Xinle; Li, Jie; Wang, Xiaoyu; Liu, Daquan; Zhai, Lidong; Ding, Beibei; Li, Guang; Sun, Yuting; Yokota, Hiroki; Zhang, Ping; Biomedical Engineering, Purdue School of Engineering and Technology
    Osteoarthritis (OA) is one of the most common chronic diseases, in which inflammatory responses in the articular cavity induce chondrocyte apoptosis and cartilage degeneration. While mechanical loading is reported to mitigate synovial inflammation, the mechanism and pathways for the loading-driven improvement of OA symptoms remain unclear. In this research, we evaluated the loading effects on the M1/M2 polarization of synovial macrophages via performing molecular, cytology, and histology analyses. In the OA groups, the cell layer of the synovial lining was enlarged with an increase in cell density. Also, M1 macrophages were polarized and pro-inflammatory cytokines were increased. In contrast, in the OA group with mechanical loading cartilage degradation was reduced and synovial inflammation was alleviated. Notably, the polarization of M1 macrophages was diminished by mechanical loading, while that of M2 macrophages was increased. Furthermore, mechanical loading decreased the levels of pro-inflammatory cytokines such as IL-1β and TNF-α and suppressed PI3K/AKT/NF-κB signaling. Consistently, NF-κB inhibited decreased the polarization of M1 macrophages in RAW264.7 macrophages. Taken together, this study demonstrates that mechanical loading changes the ratio of M1 and M2 macrophage polarization via regulating PI3K/AKT/NF-κB signaling and provides chondroprotective effects in the mouse OA model.
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    The miR-23a∼27a∼24-2 microRNA Cluster Promotes Inflammatory Polarization of Macrophages
    (The American Association of Immunologists, 2021) Boucher, Austin; Klopfenstein, Nathan; Hallas, William Morgan; Skibbe, Jennifer; Appert, Andrew; Jang, Seok Hee; Pulakanti, Kirthi; Rao, Sridhar; Cowden Dahl, Karen D.; Dahl, Richard; Microbiology and Immunology, School of Medicine
    Macrophages are critical for regulating inflammatory responses. Environmental signals polarize macrophages to either a pro-inflammatory (M1) state or an anti-inflammatory (M2) state. We observed that the microRNA cluster mirn23a, coding for miRs-23a~27a~24–2, regulates mouse macrophage polarization. Gene expression analysis of mirn23a deficient myeloid progenitors revealed a decrease in Toll like receptor and interferon signaling. Mirn23a−/− bone marrow derived macrophages (BMDMs) have an attenuated response to lipopolysaccharide (LPS) demonstrating an anti-inflammatory phenotype in mature cells. In vitro, mirn23a−/− BMDMs have decreased M1 responses and an enhanced M2 responses. Overexpression of mirn23a has the opposite effect enhancing M1 and inhibiting M2 gene expression. Interestingly expression of mirn23a miRNAs goes down with inflammatory stimulation and up with anti-inflammatory stimulation suggesting that its regulation prevents locking macrophages into polarized states. M2 polarization of tumor associated macrophages (TAMs) correlates with poor outcome for many tumors, so to determine if there was a functional consequence of mirn23a loss modulating immune cell polarization we assayed syngeneic tumor growth in wildtype and mirn23a−/− mice. Consistent with the increased anti-inflammatory/ immunosuppressive phenotype in vitro, mirn23a−/− mice inoculated with syngeneic tumor cells had worse outcomes compared to wildtype mice. Co-injecting tumor cells with mirn23a−/− BMDMs into wildtype mice phenocopied tumor growth in mirn23a−/− mice supporting a critical role for mirn23a miRNAs in macrophage mediated tumor immunity. Our data demonstrates that mirn23a regulates M1/M2 polarization and suggests that manipulation of mirn23a miRNA can be used to direct macrophage polarization to drive a desired immune response.
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    Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype
    (Frontiers, 2019-05-07) Min, Byong-Keol; Park, Sungmi; Kang, Hyeon-Ji; Kim, Dong Wook; Ham, Hye Jin; Ha, Chae-Myeong; Choi, Byung-Jun; Lee, Jung Yi; Oh, Chang Joo; Yoo, Eun Kyung; Kim, Hui Eon; Kim, Byung-Gyu; Jeon, Jae-Han; Hyeon, Do Young; Hwang, Daehee; Kim, Yong-Hoon; Lee, Chul-Ho; Lee, Taeho; Kim, Jung-whan; Choi, Yeon-Kyung; Park, Keun-Gyu; Chawla, Ajay; Lee, Jongsoon; Harris, Robert A.; Lee, In-Kyu; Biochemistry and Molecular Biology, School of Medicine
    Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.