Skip to main content

Advertisement

SpringerLink
Log in

Castor1 overexpression regulates microglia M1/M2 polarization via inhibiting mTOR pathway

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

A Correction to this article was published on 24 January 2023

This article has been updated

Abstract

Microglia are resident immune cells in the brain and are closely associated with central nervous system inflammation and neurodegenerative diseases. It is known that mammalian target of rapamycin (mTOR) pathway plays an important role in the polarization of microglia. Castor1 has been identified as the cytosolic arginine sensor for the mTOR complex 1 (mTORC1) pathway, but the role of Castor1 in microglial polarization is still unknown. The purpose of this study was to explore the regulatory effect of Castor1 on microglial polarization and the underlying mechanism. The results demonstrated that Castor1 expression was significantly decreased in lipopolysaccharides (LPS) and interferon (IFN)-γ treated microglia. Castor1 overexpression inhibited the microglia M1 polarization by reducing the expression of M1 related markers. However, the expression of M2-related genes was promoted when Castor1 was overexpressed in IL-4 treated microglia. Mechanistically, Castor1 overexpression inhibited the activation of mTOR signaling pathway. In addition, after treatment with the mTOR activator MHY1485, the inhibitory effect of Castor1 overexpression on M1 polarization was attenuated, indicating that the regulation effects of Castor1 on M1 polarization was dependent on its inhibition of mTOR pathway. We propose that Castor1-mTOR signaling pathway could be considered as a potential target for treatment and intervention of central nervous system-related diseases by regulating microglia polarization.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Code Availability

Not applicable.

Change history

References

  • Benveniste EN (1997) Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med 75:165–173

    Article  CAS  Google Scholar 

  • Chantranupong L, Scaria SM, Saxton RA, Gygi MP, Shen K, Wyant GA, Wang T, Harper JW, Gygi SP, Sabatini DM (2016) The CASTOR Proteins are arginine sensors for the mTORC1 pathway. Cell 165:153–164

    Article  CAS  Google Scholar 

  • Colonna M, Butovsky O (2017) Microglia function in the Central Nervous System during Health and Neurodegeneration. Annu Rev Immunol 35:441–468

    Article  CAS  Google Scholar 

  • Crain JM, Nikodemova M, Watters JJ (2013) Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice. J Neurosci Res 91:1143–1151

    Article  CAS  Google Scholar 

  • Du RH, Sun HB, Hu ZL, Lu M, Ding JH, Hu G (2018) Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson’s disease. Cell Death Dis 9:404

    Article  Google Scholar 

  • Du X, Xu Y, Chen S, Fang M (2020) Inhibited CSF1R Alleviates Ischemia Injury via Inhibition of Microglia M1 Polarization and NLRP3 Pathway. Neural plasticity 2020, 8825954

  • Gai Z, Wang Q, Yang C, Wang L, Deng W, Wu G (2016) Structural mechanism for the arginine sensing and regulation of CASTOR1 in the mTORC1 signaling pathway. Cell discovery 2:16051

  • Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934

    Article  CAS  Google Scholar 

  • Hickman S, Izzy S, Sen P, Morsett L, Khoury E, J (2018) Microglia in neurodegeneration. Nat Neurosci 21:1359–1369

    Article  CAS  Google Scholar 

  • Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, Khoury E, J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16:1896–1905

    Article  CAS  Google Scholar 

  • Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J (2015) Microglial and macrophage polarization—new prospects for brain repair. Nature reviews. Neurology 11, 56–64

  • Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:3063–3070

    Article  CAS  Google Scholar 

  • Hu Y, Mai W, Chen L, Cao K, Zhang B, Zhang Z, Liu Y, Lou H, Duan S, Gao Z (2020) mTOR-mediated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP. Glia 68:1031–1045

    Article  Google Scholar 

  • Keane L, Antignano I, Riechers SP, Zollinger R, Dumas AA, Offermann N, Bernis ME, Russ J, Graelmann F, McCormick PN et al (2021) mTOR-dependent translation amplifies microglia priming in aging mice. The Journal of clinical investigation 131

  • Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170

    Article  CAS  Google Scholar 

  • Li D, Wang C, Yao Y, Chen L, Liu G, Zhang R, Liu Q, Shi FD, Hao J (2016) mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 30:3388–3399

  • Li S, Hua X, Zheng M, Wu J, Ma Z, Xing X, Ma J, Zhang J, Shan C, Xu J (2021a) PLXNA2 knockdown promotes M2 microglia polarization through mTOR/STAT3 signaling to improve functional recovery in rats after cerebral ischemia/reperfusion injury. Experimental neurology 346:113854

  • Li T, Ju E, Gao SJ (2019) Kaposi sarcoma-associated herpesvirus miRNAs suppress CASTOR1-mediated mTORC1 inhibition to promote tumorigenesis. J Clin Investig 129:3310–3323

    Article  Google Scholar 

  • Li T, Wang X, Ju E, da Silva SR, Chen L, Zhang X, Wei S, Gao SJ (2021b) RNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation. Nat Commun 12:1055

    Article  CAS  Google Scholar 

  • Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJM et al (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218

    Article  CAS  Google Scholar 

  • Nguyen HM, Grössinger EM, Horiuchi M, Davis KW, Jin LW, Maezawa I, Wulff H (2017) Differential Kv1.3, KCa3.1, and Kir2.1 expression in “classically” and “alternatively” activated microglia. Glia 65:106–121

    Article  Google Scholar 

  • Saxton RA, Chantranupong L, Knockenhauer KE, Schwartz TU, Sabatini DM (2016) Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature 536:229–233

    Article  CAS  Google Scholar 

  • Saxton RA, Sabatini DM (2017) mTOR Signaling in Growth, Metabolism, and Disease. Cell 169:361–371

  • Song GJ, Nam Y, Jo M, Jung M, Koo JY, Cho W, Koh M, Park SB, Suk K (2016) A novel small-molecule agonist of PPAR-γ potentiates an anti-inflammatory M2 glial phenotype. Neuropharmacology 109:159–169

    Article  CAS  Google Scholar 

  • Srivastava IN, Shperdheja J, Baybis M, Ferguson T, Crino PB (2016) mTOR pathway inhibition prevents neuroinflammation and neuronal death in a mouse model of cerebral palsy. Neurobiol Dis 85:144–154

    Article  CAS  Google Scholar 

  • Stephenson J, Nutma E, van der Valk P, Amor S (2018) Inflammation in CNS neurodegenerative diseases. Immunology 154:204–219

    Article  CAS  Google Scholar 

  • Subhramanyam CS, Wang C, Hu Q, Dheen ST (2019) Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol 94:112–120

    Article  CAS  Google Scholar 

  • Tang Y, Le W (2016) Differential Roles of M1 and M2 microglia in neurodegenerative Diseases. Mol Neurobiol 53:1181–1194

    Article  CAS  Google Scholar 

  • Wang C, Wang Q, Lou Y, Xu J, Feng Z, Chen Y, Tang Q, Zheng G, Zhang Z, Wu Y et al (2018) Salidroside attenuates neuroinflammation and improves functional recovery after spinal cord injury through microglia polarization regulation. J Cell Mol Med 22:1148–1166

    CAS  Google Scholar 

  • Wang G, Shi Y, Jiang X, Leak RK, Hu X, Wu Y, Pu H, Li WW, Tang B, Wang Y et al (2015) HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis. Proc Natl Acad Sci USA 112:2853–2858

    Article  CAS  Google Scholar 

  • Xiao Q, Yu W, Tian Q, Fu X, Wang X, Gu M, Lü Y (2017) Chitinase1 contributed to a potential protection via microglia polarization and Aβ oligomer reduction in D-galactose and aluminum-induced rat model with cognitive impairments. Neuroscience 355:61–70

    Article  CAS  Google Scholar 

  • Yang Y, Ye Y, Kong C, Su X, Zhang X, Bai W, He X (2019) MiR-124 enriched Exosomes promoted the M2 polarization of Microglia and enhanced Hippocampus Neurogenesis after Traumatic Brain Injury by inhibiting TLR4 pathway. Neurochem Res 44:811–828

    Article  CAS  Google Scholar 

  • Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, Vyssotski AL, Bifone A, Gozzi A, Ragozzino D et al (2014) Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 17:400–406

    Article  CAS  Google Scholar 

  • Zhao XF, Liao Y, Alam MM, Mathur R, Feustel P, Mazurkiewicz JE, Adamo MA, Zhu XC, Huang Y (2020) Microglial mTOR is neuronal protective and antiepileptogenic in the Pilocarpine model of temporal lobe Epilepsy. J neuroscience: official J Soc Neurosci 40:7593–7608

    Article  CAS  Google Scholar 

  • Zhou X, Cheng Z, Chen H, Shi S, Wang X, Orang M, Zhao J (2018a) CASTOR1 suppresses the progression of lung adenocarcinoma and predicts poor prognosis. J Cell Biochem 119:10186–10194

    Article  CAS  Google Scholar 

  • Zhou Y, Ulland TK, Colonna M (2018b) TREM2-Dependent Effects on Microglia in Alzheimer’s Disease. Front Aging Neurosci 10:202

    Article  Google Scholar 

  • Zhuang X, Yu Y, Jiang Y, Zhao S, Wang Y, Su L, Xie K, Yu Y, Lu Y, Lv G (2020) Molecular hydrogen attenuates sepsis-induced neuroinflammation through regulation of microglia polarization through an mTOR-autophagy-dependent pathway. Int Immunopharmacol 81:106287

    Article  CAS  Google Scholar 

  • Zhuang Y, Wang XX, He J, He S, Yin Y (2019) Recent advances in understanding of amino acid signaling to mTORC1 activation. Frontiers in bioscience (Landmark edition). 24:971–982

Download references

Acknowledgements

We thank Dr. Jing Li at First Affiliated Hospital of Bengbu Medical College and Dr. Xiaoting Xu at Sun Yat-Sen University for kindly providing technical supports and suggestions about flow cytometry experiments.

Funding

This work was supported by National Natural Science Foundation of China (82000803, 82100921), Guangdong Basic and Applied Basic Research Foundation (2019A1515010980, 2020A1515011467), the Fundamental Research Funds for the Central Universities (20ykpy96), Guangzhou Science and Technology Plan Project (202102021099, 202201010994).

Author information

Author notes

  1. These authors (Huiling Hu, Xiaoxia Lu, and Lisi Huang) contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Huiling Hu, Xiaoxia Lu, Lisi Huang, Xiuli Liu, Ying Wang & Chaohui Duan

  2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Huiling Hu, Xiaoxia Lu, Lisi Huang, Xiuli Liu, Ying Wang & Chaohui Duan

  3. Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Yuqing He

Authors
  1. Huiling Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoxia Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuqing He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiuli Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chaohui Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Huiling Hu and Chaohui Duan contributed to the study conception and design. Material preparation, data collection and analysis were performed by Huiling Hu, Xiaoxia Lu and Yuqing He. The first draft of the manuscript was written by Huiling Hu, Xiaoxia Lu and Xiuli Liu. Lisi Huang and Ying Wang contributed to the revision of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Huiling Hu, Ying Wang or Chaohui Duan.

Ethics declarations

Conflict of interest

The authors have no conflict or competing interests.

Ethical approval

All experimental procedures with animals were approved by the Institutional Animal Care and Use Committee of the Sun Yat-sen University.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, H., Lu, X., Huang, L. et al. Castor1 overexpression regulates microglia M1/M2 polarization via inhibiting mTOR pathway. Metab Brain Dis 38, 699–708 (2023). https://doi.org/10.1007/s11011-022-01135-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-022-01135-w

Keywords

Search

Navigation