Echinococcus multilocularis protoscoleces enhance glycolysis to promote M2 Macrophages through PI3K/Akt/mTOR Signaling Pathway

doi:10.21203/rs.3.rs-1665573/v1

Download PDF

Research Article

Echinococcus multilocularis protoscoleces enhance glycolysis to promote M2 Macrophages through PI3K/Akt/mTOR Signaling Pathway

https://doi.org/10.21203/rs.3.rs-1665573/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: Alveolar Echinococcosis (AE) is a zoonotic parasitic disease caused by Echinococcus multilocularis, but its pathogenesis remains unclear. The primary objective of this study is to explore whether Echinococcus multilocularis protoscoleces (PSCs) regulate macrophage polarization and glucose metabolism by PI3K/Akt/mTOR signaling pathway.

Methods: Macrophage polarization were analyzed by flow cytometry, PI3K, Akt, pAKT, and mTOR were detected by western blot, and cell metabolic was analyzed by seahorse.

Results: Large numbers of CD68⁺ macrophages gathered in close liver issue from the lesion in AE patients. PSCs preferentially differentiated into M2 macrophages and the expressions of HK1, PFKL, PKM2, PI3K, pAKT, and mTOR increased with the extension of co-culture time.

Conclusions: Echinococcus multilocularis protoscoleces enhance glycolysis to promote M2 macrophages through PI3K/Akt/mTOR signaling pathway.

Echinococcus multilocularis

Glycolysis

Macrophage polarization

Protoscoleces

PI3K/Akt/mTOR

Alveolar Echinococcosis (AE) is a zoonotic parasitic disease caused by Echinococcus multilocularis (E. multilocularis), which is widely distributed in northern Hemisphere, such as western China, Canada, France and Germany[1, 2]. AE was one of the most important infectious diseases on the Tibetan Plateau (such as Qinghai, Tibet, Sichuan and Xinjiang), 91% of the new AE cases in the world came from China, and 90% of them were from the Tibetan Plateau[3–5]. The growth of Alveolar Echinococcosis lesions is invasive in the host body, as newly diagnosed AE patients usually have reached an advanced stage and the death rate of patients in 10 years without treatment could reach 90%[5, 6], so it also called “worm cancer”[7]. Therefore, AE is considered to be one of the most lethal chronic parasitosis diseases and seriously threat to life and health[1, 8, 9].

Macrophages coordinate proinflammatory and anti-inflammatory responses to infection and play an important role in the maintenance of cell homeostasis and repair. Parasitic infection was related to the macrophage polarization patterns[10–13]. Previous studies have found that numerous macrophages gathered around the lesion in AE patients, but the disease was still getting worse, and both M1 and M2 macrophages were significantly higher in close liver issue (CLT) than in distant liver tissue (DLT) from the lesion[12]. Pathogen infection modulated macrophages polarization through metabolic reprogramming by the PI3K/Akt/mTOR signaling pathway[14, 15]. E. multilocularis infection changed glucose metabolism, macrophage polarization and PI3K/Akt/mTOR signaling pathways[11, 12, 16]. PI3K/Akt/mTOR signaling pathway promote M2 Polarization by increasing glucose uptake, intracellular ATP and changing glucose metabolism[17, 18].Therefore, clarifying E. multilocularis protoscoleces (PSCs)enhance glycolysis to promote M2 macrophages through PI3K/Akt/mTOR signaling pathway may help us to understand the pathogenesis of AE.

In this study, E. multilocularis PSCs were cultured with Raw264.7 to investigate whether PSCs regulate macrophage polarization and glucose metabolism through PI3K/Akt/mTOR signaling pathway, which may provide a new treatment strategy for clinical AE treatment.

Human Subjects

AE patients included in this study were diagnosed with ultrasound, computed tomography and biopsy in Qinghai University Affiliated Hospital. The study complied with the ethical approval of the Qinghai University Affiliated Hospital (P-SL-2019033) and the Helsinki Declaration of 1975. All AE patients had given informed consent.

Cell Culture

The murine macrophages cell line Raw264.7 were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). Raw264.7 were cultured in DMEM supplemented with 10% fetal bovine serum at 37℃ in 5% CO2 incubator.

Isolation and cultured E. multilocularis PSCs

The AE cysts were collected from mongolian gerbils infected with E. multilocularis PSCs. The AE cysts cut into small pieces and passed through 300um and 80um aseptic sieves to collect the PSCs. The viability of PSCs was tested by 0.1% trypan blue, only PSCs exhibiting over 90% viability were counted and subsequently used to coculture with Raw264.7. PSCs were cultured in DMEM supplemented with 20% fetal bovine serum.

PSCs infections and macrophage phagocytosis

Raw264.7 were cocultured with PSCs at the ratio of 500:1. Raw264.7 were seeded in 6-well plates with 1.0*10⁵cells/well for overnight. After that, Raw264.7 were cocultured with PSCs for 24h, 48h, and 72h in the antibiotic free cell culture medium. After that, Raw264.7 were infected at a multiplicity of infection (MOI) 10:1 (Escherichia coli/cell) with PSCs, and each well was washed three times with PBS to remove the extracellular Escherichia coli. 50μL cell suspension and the third time PBS were added to LB medium, and next day colony-forming units were counted.

Flow Cytometric Analysis

The coculture Raw264.7 were collected to flow cytometric analysis, and 5*105 cells were used to perform each assay in triplicate. According to the manufacturer’s instruction, FITC Rat Anti-Mouse CD86 (561962, BD) and PE Anti-Mouse CD206 (141706, BD) were utilized to examine macrophage polarization.

Cell Metabolic Assays

Raw264.7 were seeded in seahorse XF 96-well with1.0*10⁴/per well and cocultured with 1.2μM in quadruplicate. The XF Cell Mito Stress Test kit (Cat#103015-100) was used to assay glycolysis and mitochondrial metabolism.

Western blot analysis

Whole cell proteins were lysed with RIPA buffer containing protease and phosphatase inhibitors. 15μg of total protein were loaded onto an 10% SDS-acrylamide gel, ran at 60mA for 1.5h, transferred to a PVDF membranes for 2.5h, and then blocked with 10% skim milk at room temperature for 1h. Membranes were incubated with the primary antibodies (PI3K, 1:500, GB11525, servicebio; Akt, 1:1000, GB11689, servicebio; pAKT,1:2000, CST4060s, cell signaling technology; mTOR, 1:10000, 66888-1-Ig, proteintech) for overnight at 4℃, and then incubated with secondary antibodies at room temperature (RT) for 1h. Hypersensitive Chemiluminescence kit was used to detect protein signals.

Immunohistochemical staining

Liver tissue samples were taken from AE patients, which were close liver tissue (CLT) and distant liver tissue (DLT) from the lesion. Liver tissue were formalin-fixed, paraffin-embedded, and sectioned with 3μm. For immunohistochemical (IHC) staining, slices were incubated with CD68 (1:200, NB100-683, Novus biologicals) antibody overnight at 4 °C, and then incubated with the secondary antibody for 1h at RT. Visualization was induced with a diaminobenzidine substrate kit, and then all images were acquired by Tissue FAXS PLUS system (Tissue Gnostics, Austria).

Immunofluorescence

Raw264.7 were cultured on glass coverslip in complete medium in 6-well cell culture plates overnight, and were co-cultured with PSCs for 24h, 48h, 72h. Cells were washed third times with PBS, fixed with 4% formaldehyde for 10min, permeabilized with 1% NP-40 for 5min, and blocked with 5% BSA for 2h at RT. Cells incubated with mTOR (1:100, 66888-1-Ig, proteintech) for 1h at RT, incubated with secondary antibodies for 1h at room temperature, incubated with DAPI for 10min and observation with Tissue FAXS PLUS system (Tissue Gnostics, Austria).

Statistical analysis

Results are presented as the mean ± SD. Results were analyzed by GraphPad Prism 8.0 software and Statistical significance was determined by using unpaired t-test (two-tailed) and differences among normally distributed values of 3 or more experimental groups were analyzed by one-way ANOVA, followed by a Fisher’s LSD text. Values of P < 0.05 were considered statistically significant. (*P < 0.05, ** P < 0.01, *** P < 0.001.)

Macrophages accumulate around the liver lesion in AE patients

Macrophages played an important role in cell homeostasis and repair. To investigate the characteristics of hepatic macrophages in AE patients (n=10), we examined the expression of CD68 (a marker indicating total macrophages) in AE patient liver specimens by IHC staining. We found that the number of CD68⁺ macrophages in CLT was higher than that in DLT (t-test, t₍₄₎=30.04, P < 0.001) (Fig. 1), but the proliferation of macrophages did not prevent AE progression, so we speculated that the function of macrophages could be inhibited by PSCs infection.

PSCs inhibit macrophage phagocytosis and differentiate into to M2 macrophage

To verify inhibition of macrophage function, we examined macrophage phagocytosis and macrophage phenotypes. We found the phagocytosis of Escherichia coli was significantly reduced when Raw264.7 were cocultured with PSCs (Fig. 2a-c), which suggesting that PSCs inhibited macrophages phagocytosis. To characterize the functional phenotype of hepatic macrophages, next we detected M1 macrophage and M2 macrophage levels by flow cytometry. We found that M1 macrophages decreased (co-culture 24h vs control-24h: Fisher’s LSD text, t=3.695, P=0.003; co-culture 72h vs control-72h: Fisher’s LSD text, t=8.528, P < 0.001) (Fig. 2e) and M2 macrophages increased (co-culture 24h vs control-24h: Fisher’s LSD text, t=3.319, P=0.006; co-culture 48h vs control-48h: Fisher’s LSD text, t=3.017, P=0.017; co-culture 72h vs control-72h: Fisher’s LSD text, t=4.709, P < 0.001) (Fig. 2f) when Raw264.7 were co-cultured with PSCs, which suggesting that PSCs could preferentially differentiate into M2 macrophages.

PSCs enhance macrophage glycolysis

Previous studies have found metabolic reprogramming altered macrophage polarization. To investigate whether PSCs altered glucose metabolism patterns, we used western blot to measure glycolysis key enzyme expression. We found that the expressions of hexokinase 1 (HK1), phosphofructokinase (PFKL) and pyruvate Kinase M2 (PKM2) increased with the extension of co-culture time (Fig. 3a). In addition, we used Seahorse X96 to perform mitochondrial stress test on macrophages co-cultured with PSCs for 24h, 48h, and 72h, and the results showed that aerobic respiration capacity of mitochondria decreased (Fig. 3b), and the ATP production (ANOVA, F_(4,9)=41.76, P < 0.001) (Fig. 3h) decreased with the prolonged time of multilocular cyst fluid (MCF) infection. These results indicated that mitochondrial oxidative phosphorylation of macrophages decreased and glycolysis capacity increased. The above results suggested that the metabolic type of macrophages changed to glycolysis.

Effect of PSCs on PI3K/Akt/mTOR Signaling Pathway

PI3K/Akt/mTOR signaling pathway was able to modulate macrophages polarization by regulating glucose metabolism, therefore western blot was conducted to analyze the expression of PI3K, Akt and mTOR. We found that the expression of PI3K, pAkt and mTOR decreased when Raw264.7 were co-cultured with PSCs for 24h, while PI3K, pAkt and mTOR increased with the extension of co-culture time (Fig. 4a, b). We also found that mTOR increased with the prolongation time of co-culture compared with control (Fig. 4c). The results showed that the PI3K/AKT/mTOR signaling pathway was activated after PSCs infection.

The best evidence for the immunomodulatory effect of echinococcus infection on inflammatory disease in its murine intermediate host has been confirmed by colitis model[19, 20]. We found large numbers of macrophages gathered around the lesion, but their function was limited. Parasitic infection was closely related to different macrophages polarization types[10, 13, 21]. In the early stages of parasitic infection, hepatic macrophages were preferentially differentiated into M1 macrophages, and both M1 macrophages and M2 macrophages were significantly increased during the mature stage[10, 21]. Macrophage polarization could be induced by neotropical Leishmania infection, the level of M1 macrophages increased in nonulcerated cutaneous leishmaniasis, and M2 macrophages significantly increased in the skin lesions of patients with anergic diffuse cutaneous leishmaniasis[13]. Macrophages preferentially differentiated into the M1 macrophages during the acute stage of Schistosoma japonicum infection. On the other hand, M1 macrophages decreased and M2 macrophages significantly increased during the chronic stage of infection[21]. Therefore, different macrophages polarization was closely related to disease progression. In Multilocular echinococcus infection mice model, macrophages preferentially differentiated into M1 macrophages in the early stage, while macrophages were polarized to M2 macrophages during chronic infection[12]. When Raw264.7 were cocultured with PSCs, we also found that macrophages gradually polarized to M2 macrophages.

There were significant differences in metabolism between M1 and M2 macrophages, indicating that the polarity of macrophages was closely related to cell metabolism[22]. M1 macrophages mainly dependent on glycolysis, tricarboxylic acid cycle and mitochondrial oxidative phosphorylation (OXPHOS) were impaired, but M2 macrophages were more dependent on OXPHOS[23]. Compared with M2 macrophages, M1 macrophages had higher aerobic glycolysis rate and higher gene expression of glycolysis enzyme[22]. Knocking down pyruvate dehydrogenase kinase 1 increased mitochondrial respiration, reduced M1 macrophages and enhanced M2 macrophages[24].

Macrophages infected with leishmania preferentially upregulate oxidative phosphorylation[25], and (1)H NMR-based metabolomics study of AE patients showed that the metabolism of glucose and amino acids was disorder, the oxidative capacity of fatty acids was reduced[16], which suggesting that the changes of glucose metabolism were caused by parasitic infection. We found that the level of mitochondrial oxidative phosphorylation decreased and glycolysis increased during the extension of MCF infection time. What’s more, we found that HK1, PFKL and pyruvate PKM2 increased with the extension of PSCs co-culture time, which suggest that PSCs enhanced glycolysis level. Therefore, we hypothesized that PSCs induced to M2 macrophages by increasing glycolysis.

PI3K/Akt signaling pathway regulated the glycolysis by inducing the expression of Glucose transporter 1, and regulating the activity of glycolytic enzymes (HK, PFK) expression[26, 27]. Mycobacterium tuberculosis Rv1987 protein and HSPA12B secreted by tumor-associated endothelial cells induced M2 macrophages through activating the PI3K/Akt1/mTOR signaling pathway[28, 29]. Human herpesvirus 6A increased expressions of the key glucose transporters and glycolytic enzymes, and 2-Deoxy-D-glucose inhibited of glycolysis and mTORC1 activity[30] Macrophages in chronic non-eosinophilic sinusitis with nasal polyps were preferentially differentiated into M1 Macrophages through the mTOR/HIF1α/VEGF signaling pathway[31]. The secretion of the fourth-stage larval Angiostrongylus cantonensis inhibited glycolysis and induced to M2 macrophages through PI3K/Akt pathway[14]. Pseudomonas aeruginosa induced to M1 macrophages and increased glycolysis of tumor-associated macrophages ability[15]. Previous studies have found that PI3K/Akt/mTOR signaling pathway could regulate macrophage polarization by metabolism reprogramming[32–35]. Echinococcus granulosus infection and ES products, induced peritoneal macrophages recruitment and alternative activation through the PI3K/AKT/mTOR pathway[11]. We found that the expression of PI3K, pAKT, mTOR was increased with the extension of co-culture time, which suggesting that PSCs infection activated the PI3K/AKT/mTOR signaling pathway. The above results showed that PSCs enhanced glycolysis to promote M2 Macrophages through PI3K/Akt/mTOR Signaling Pathway.

In this study, we found that the polarization type of macrophages, the type of glucose metabolism, and the expression of PI3K, pAKT and mTOR were changed after PSCs infection. Our results implied that PSCs enhanced glycolysis to promote M2 Macrophages through PI3K/Akt/mTOR Signaling Pathway, which might reveal the pathogenesis of AE and provide a new idea of prevention and treatment strategies for AE.

AE: Alveolar Echinococcosis; CLT: close liver tissue; DLT: distant liver tissue; PSCs: protoscoleces; IHC: immunohistochemical; HK1: hexokinase 1; PFKL: phosphofructokinase; PKM2: pyruvate Kinase M2; MCF: multilocular cyst fluid; OXPHOS: oxidative phosphorylation.

Acknowledgments

We thank the Qinghai province Research Key Laboratory for Echinococcosis.

Funding

This study was supported by National Natural Science Foundation of China (grant 8196031000), the Science and Qinghai Science and Technology Department Project (grant 2021-SF-135) and Young and middle-aged Scientific Research Fund of Qinghai University Affiliated Hospital (grant ASRF-2020-YB-07).

Availability of data and materials

The datasets used and/or analyzed in this study are available from the corresponding author on reasonable request.

Authors’ contributions

ZT performed the experiments and wrote this manuscript. ZYG and YZH collected AE liver tissue samples. JY and SL analyzed the data. HDL and TMY performed the experiments. SYH and DJ helped to perform the experiments and manuscript preparation. JH and YYM conceived and designed the study. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

This study was approved by the ethical approval of the Qinghai University Affiliated Hospital (P-SL-2019033).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conﬂict of interest.

Author details

¹Research Center for High Altitude Medicine, Qinghai university, Xining 810001, Qinghai Province, China; ²Key Laboratory of Application of High Altitude Medicine in Qinghai, Qinghai university, Xining 810001, Qinghai Province, China; ³Department of rehabilitation medicine, Qinghai University Affiliated Hospital, Xining 810001, Qinghai Province, China; ⁴Central Laboratory of Qinghai University Affiliated Hospital, Affiliated Hospital of Qinghai University, Xining 810001, Qinghai Province, China; ⁵Qinghai Province Research Key Laboratory of Echinococcosis, Qinghai University Affiliated Hospital, Xining 810001, Qinghai Province, China;⁶Department of Neurology, Qinghai University Affiliated Hospital, Xining 810001, Qinghai Province, China;⁷Department of Pediatrics, Qinghai University Affiliated Hospital, Xining 810001, Qinghai Province, China.

Wang Q, Yang L, Wang Y, Zhang GJ, Zhong B, Wu WP, et al. Disease burden of echinococcosis in Tibetan communities-A significant public health issue in an underdeveloped region of western China. Acta Trop. 2020;203:105283.
Woolsey ID, Miller AL. Echinococcus granulosus sensu lato and Echinococcus multilocularis: A review. Res Vet Sci. 2021;135:517-22.
Barnes AN, Davaasuren A, Baasandagva U, Gray GC. A systematic review of zoonotic enteric parasitic diseases among nomadic and pastoral people. PLoS One. 2017;12:e0188809.
Wen H, Vuitton L, Tuxun T, Li J, Vuitton DA, Zhang W, et al. Echinococcosis: Advances in the 21st Century. Clin Microbiol Rev. 2019;32.
Fu MH, Wang X, Han S, Guan YY, Bergquist R, Wu WP. Advances in research on echinococcoses epidemiology in China. Acta Trop. 2021;219:105921.
Craig PS, Giraudoux P, Wang ZH, Wang Q. Echinococcosis transmission on the Tibetan Plateau. Adv Parasitol. 2019;104:165-246.
Qucuo N, Wu G, He R, Quzhen D, Zhuoga C, Deji S, et al. Knowledge, attitudes and practices regarding echinococcosis in Xizang Autonomous Region, China. BMC Public Health. 2020;20:483.
Dezsényi B, Dubóczki Z, Strausz T, Csulak E, Czoma V, Káposztás Z, et al. Emerging human alveolar echinococcosis in Hungary (2003-2018): a retrospective case series analysis from a multi-centre study. BMC Infect Dis. 2021;21:168.
Yangdan CR, Wang C, Zhang LQ, Ren B, Fan HN, Lu MD. Recent advances in ultrasound in the diagnosis and evaluation of the activity of hepatic alveolar echinococcosis. Parasitol Res. 2021;120:3077-82.
Kim EM, Kwak YS, Yi MH, Kim JY, Sohn WM, Yong TS. Clonorchis sinensis antigens alter hepatic macrophage polarization in vitro and in vivo. PLoS Negl Trop Dis. 2017;11:e0005614.
Wang H, Zhang CS, Fang BB, Li ZD, Li L, Bi XJ, et al. Thioredoxin peroxidase secreted by Echinococcus granulosus (sensu stricto) promotes the alternative activation of macrophages via PI3K/AKT/mTOR pathway. Parasit Vectors. 2019;12:542.
Wang H, Zhang CS, Fang BB, Hou J, Li WD, Li ZD, et al. Dual Role of Hepatic Macrophages in the Establishment of the Echinococcus multilocularis Metacestode in Mice. Front Immunol. 2020;11:600635.
Sandoval Pacheco CM, Araujo Flores GV, Gonzalez K, de Castro Gomes CM, Passero L, Tomokane TY, et al. Macrophage Polarization in the Skin Lesion Caused by Neotropical Species of Leishmania sp. J Immunol Res. 2021;2021:5596876.
Wan S, Sun X, Tang W, Wang L, Wu Z, Sun X. Exosome-Depleted Excretory-Secretory Products of the Fourth-Stage Larval Angiostrongylus cantonensis Promotes Alternative Activation of Macrophages Through Metabolic Reprogramming by the PI3K-Akt Pathway. Front Immunol. 2021;12:685984.
Yu H, Bai Y, Qiu J, He X, Xiong J, Dai Q, et al. Pseudomonas aeruginosa PcrV Enhances the Nitric Oxide-Mediated Tumoricidal Activity of Tumor-Associated Macrophages via a TLR4/PI3K/AKT/mTOR-Glycolysis-Nitric Oxide Circuit. Front Oncol. 2021;11:736882.
Lin C, Chen Z, Zhang L, Wei Z, Cheng KK, Liu Y, et al. Deciphering the metabolic perturbation in hepatic alveolar echinococcosis: a (1)H NMR-based metabolomics study. Parasit Vectors. 2019;12:300.
Lian G, Chen S, Ouyang M, Li F, Chen L, Yang J. Colon Cancer Cell Secretes EGF to Promote M2 Polarization of TAM Through EGFR/PI3K/AKT/mTOR Pathway. Technol Cancer Res Treat. 2019;18:1533033819849068.
Liao S, Liang L, Yue C, He J, He Z, Jin X, et al. CD38 is involved in cell energy metabolism via activating the PI3K/AKT/mTOR signaling pathway in cervical cancer cells. Int J Oncol. 2020;57:338-54.
Khelifi L, Soufli I, Labsi M, Touil-Boukoffa C. Immune-protective effect of echinococcosis on colitis experimental model is dependent of down regulation of TNF-α and NO production. Acta Trop. 2017;166:7-15.
Wang J, Goepfert C, Mueller N, Piersigilli A, Lin R, Wen H, et al. Larval Echinococcus multilocularis infection reduces dextran sulphate sodium-induced colitis in mice by attenuating T helper type 1/type 17-mediated immune reactions. Immunology. 2018;154:76-88.
Zhu J, Xu Z, Chen X, Zhou S, Zhang W, Chi Y, et al. Parasitic antigens alter macrophage polarization during Schistosoma japonicum infection in mice. Parasit Vectors. 2014;7:122.
Qing J, Zhang Z, Novák P, Zhao G, Yin K. Mitochondrial metabolism in regulating macrophage polarization: an emerging regulator of metabolic inflammatory diseases. Acta Biochim Biophys Sin (Shanghai). 2020;52:917-26.
Diskin C, Pålsson-McDermott EM. Metabolic Modulation in Macrophage Effector Function. Front Immunol. 2018;9:270.
Li C, Ding XY, Xiang DM, Xu J, Huang XL, Hou FF, et al. Enhanced M1 and Impaired M2 Macrophage Polarization and Reduced Mitochondrial Biogenesis via Inhibition of AMP Kinase in Chronic Kidney Disease. Cell Physiol Biochem. 2015;36:358-72.
Ty MC, Loke P, Alberola J, Rodriguez A, Rodriguez-Cortes A. Immuno-metabolic profile of human macrophages after Leishmania and Trypanosoma cruzi infection. PLoS One. 2019;14:e0225588.
Melstrom LG, Salabat MR, Ding XZ, Milam BM, Strouch M, Pelling JC, et al. Apigenin inhibits the GLUT-1 glucose transporter and the phosphoinositide 3-kinase/Akt pathway in human pancreatic cancer cells. Pancreas. 2008;37:426-31.
Feng J, Li J, Wu L, Yu Q, Ji J, Wu J, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2020;39:126.
Zhou J, Zhang A, Fan L. HSPA12B Secreted by Tumor-Associated Endothelial Cells Might Induce M2 Polarization of Macrophages via Activating PI3K/Akt/mTOR Signaling. Onco Targets Ther. 2020;13:9103-11.
Sha S, Shi Y, Tang Y, Jia L, Han X, Liu Y, et al. Mycobacterium tuberculosis Rv1987 protein induces M2 polarization of macrophages through activating the PI3K/Akt1/mTOR signaling pathway. Immunol Cell Biol. 2021;99:570-85.
Wu Z, Jia J, Xu X, Xu M, Peng G, Ma J, et al. Human herpesvirus 6A promotes glycolysis in infected T cells by activation of mTOR signaling. PLoS Pathog. 2020;16:e1008568.
Zhong B, Du J, Liu F, Liu Y, Liu S, Xie L, et al. Activation of the mTOR/HIF-1α/VEGF axis promotes M1 macrophage polarization in non-eosinophilic chronic rhinosinusitis with nasal polyps. Allergy. 2022;77:643-6.
Bhattacharya B, Mohd Omar MF, Soong R. The Warburg effect and drug resistance. Br J Pharmacol. 2016;173:970-9.
Shang RZ, Qu SB, Wang DS. Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects. World J Gastroenterol. 2016;22:9933-43.
Wang P, Cong M, Liu T, Li Y, Liu L, Sun S, et al. FoxA2 inhibits the proliferation of hepatic progenitor cells by reducing PI3K/Akt/HK2-mediated glycolysis. J Cell Physiol. 2020;235:9524-37.
Li Q, Wu W, Gong D, Shang R, Wang J, Yu H. Propionibacterium acnes overabundance in gastric cancer promote M2 polarization of macrophages via a TLR4/PI3K/Akt signaling. Gastric Cancer. 2021;24:1242-53.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Echinococcus multilocularis protoscoleces enhance glycolysis to promote M2 Macrophages through PI3K/Akt/mTOR Signaling Pathway

Status:

Version 1

Abstract

Figures

Background

Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1