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Small molecule disruption of G protein ?? subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats.

ABSTRACT: The purpose of this study was to determine whether blocking of G protein ?? (G??) signaling halts heart failure (HF) progression by macrophage phenotype manipulation. Cardiac G?? signaling plays a crucial role in HF pathogenesis. Previous data suggested that inhibiting G?? signaling reprograms T helper cell 1 (Th1) and Th2 cytokines, suggesting that G?? might be a useful drug target for treating HF. We investigated the efficacy of a small molecule G?? inhibitor, gallein, in a clinically relevant, experimental autoimmune myocarditis (EAM) model of HF as well as in human macrophage phenotypes in vitro. In the myocardium of HF patients, we observed that G protein coupled receptor kinase (GRK)2 levels were down-regulated compared with healthy controls. In rat EAM, treatment with gallein effectively improved survival and cardiac function, suppressed cardiac remodeling, and further attenuated myocardial protein expression of GRK2 as well as high mobility group box (HMGB)1 and its cascade signaling proteins. Furthermore, gallein effectively inhibited M1 polarization and promoted M2 polarization in vivo in the EAM heart and in vitro in human monocyte-derived macrophages. Taken together, these data suggest that the small molecule G?? inhibitor, gallein, could be an important pharmacologic therapy for HF as it can switch the phenotypic reprogramming from M1 to M2 phenotype in a rat model of EAM heart and in human macrophages.

SUBMITTER: Karuppagounder V

PROVIDER: S-EPMC6053176 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats.

Karuppagounder Vengadeshprabhu V Bajpai Anamika A Meng Shu S Arumugam Somasundaram S Sreedhar Remya R Giridharan Vijayasree V VV Guha Ashrith A Bhimaraj Arvind A Youker Keith A KA Palaniyandi Suresh S SS Karmouty-Quintana Harry H Kamal Fadia F Spiller Kara L KL Watanabe Kenichi K Thandavarayan Rajarajan A RA

PloS one 20180719 7

The purpose of this study was to determine whether blocking of G protein βγ (Gβγ) signaling halts heart failure (HF) progression by macrophage phenotype manipulation. Cardiac Gβγ signaling plays a crucial role in HF pathogenesis. Previous data suggested that inhibiting Gβγ signaling reprograms T helper cell 1 (Th1) and Th2 cytokines, suggesting that Gβγ might be a useful drug target for treating HF. We investigated the efficacy of a small molecule Gβγ inhibitor, gallein, in a clinically relevant ...[more]

PMID: 30024944

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Project description:Accumulating evidence has shown that tumor-associated macrophages (TAMs) play a critical role in tumor progression. Targeting TAMs is a potential strategy for tumor immunotherapy. However, the mechanism underlying the TAM phenotype and function needs to be resolved. Our previous studies have demonstrated that miR-125a can reverse the TAM phenotype toward antitumor. Meanwhile, we have found that miR-125a and miR-99b cluster in the first intron of the same host gene, and are transcribed simultaneously in bone marrow-derived macrophages (BMDMs) following LPS+IFNγ stimulation. However, it remains unclear whether miR-99b by itself can exert an antitumor effect by regulating macrophage phenotype. miR-99b and/or miR-125a were delivered into TAMs of orthotopic hepatocellular carcinoma (HCC) or subcutaneous Lewis lung cancer (LLC) mice. The effect of treatment was evaluated by live imaging, TUNEL staining and survival tests. The phenotype of the immune cells was determined by qRT-PCR, ELISA, western blot and FACS. The capability of miR-99b-mediated macrophage phagocytosis and antigen presentation was detected by FACS and immunofluorescence staining. The underlying molecular mechanism was examined by qRT-PCR, reporter assay and western blot, and further verified in the tumor model. The expression of miR-99b and its target genes was determined in TAMs sorted from tumor and adjacent tissues in patients with liver cancer. Targeted delivery of miR-99b and/or miR-125a into TAMs significantly impeded the growth of HCC and LLC, especially after miR-99b delivery. More importantly, the delivery of miR-99b re-educated TAM toward antitumor phenotype with enhanced immune surveillance. Further investigation of mechanisms showed that macrophage-specific overexpression of miR-99b promoted M1 while suppressing M2 macrophage polarization by targeting κB-Ras2 and/or mTOR, respectively. miR-99b-overexpressed M1 macrophage was characterized by stronger capability of phagocytosis and antigen presentation. Additionally, delivery of simTOR or siκB-Ras2 into TAMs inhibited miR-99b antagomir-triggered tumor growth. Finally, miR-99b expression was lower in TAMs of patients with liver cancer than that in adjacent tissues, while the expression of κB-Ras2 and mTOR was reversed. Our results reveal the mechanism of miR-99b-mediated TAM phenotype, indicating that TAM-targeted delivery of miR-99b is a potential strategy for cancer immunotherapy.

Dataset Information

Small molecule disruption of G protein ?? subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats.

Publications

Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats.

Similar Datasets

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