Skip to main content

Advertisement

SpringerLink
Log in

MiR-145 improves macrophage-mediated inflammation through targeting Arf6

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

To explore the relationship between miR-145 and ADP ribosylation factor 6 (Arf6) in regulating macrophage-mediated inflammation.

Methods

THP-1 cells were induced by 160 nM of phorbol 12−myristate 13-acetate (PMA) for 48 h to differentiate to macrophages and then were treated with LPS (100 ng/ml) for 8 h to simulate chronic metabolic inflammation in vitro. Dual-luciferase reporter assay was performed. MiR-145 siRNA and LV-ARF6-RNAi were used to up or down regulate miR-145 and Arf6 expression in THP-1 cells, respectively. Omental adipose tissue from patients in surgical ward were collected to detect the expression of miR-145, Arf6 and production of proinflammatory cytokines. Patients were divided into three groups according to their body mass index and history of diabetes.

Results

Dual-luciferase reporter assays showed the direct down-regulation of Arf6 by miR-145. Forty-eight-hour-transfection of miR-145 inhibitor resulted in significant increase of Arf6, IL-1beta, TNF-alpha and IL-6 as well as phosphorylation of p65 in NF-kappaB pathway in THP-1 cells, which, inversely, were reversed by overexpressing miR-145. In addition, down-regulation of Arf6 in macrophages reduced expression and secretion of cytokines. Expression of miR-145 was found to be attenuated in the omental adipose tissue of obese patients and diabetics with greater Arf6 expression, confirming the role of miR-145 in regulating macrophage-mediated inflammation targeting Arf6.

Conclusions

By means of reducing the expression of Arf6 and subsequent signal transduction via NF-kappaB, miR-145 plays a role in inhibiting the secretion of inflammatory factors and then improving the inflammatory status. MiR-145 might be one of the candidates for anti-inflammatory treatment for metabolic diseases.

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.

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

Similar content being viewed by others

References

  1. International Diabetes Federation (IDF), Diabetes Atlas. 7th edn. Canada, (2015). www.diabetesatlas.org

  2. J.C. Pickup, M.B. Mattock, G.D. Chusney, D. Burt, NIDDM as a disease of the innate immune systemassociation of acute-phase reactants and interleukin-6 with metabolicsyndromeX. Diabetologia 40, 1286–1292 (1997)

    Article  CAS  PubMed  Google Scholar 

  3. M. Rodriguez-Moran, F. Guerrero-Romero, Increased levels of C-reactive protein in noncontrolled type II diabetic subjects. J. Diabetes Complicat. 13(4), 211–215 (1999)

    Article  CAS  PubMed  Google Scholar 

  4. P.D. Cani, R. Bibiloni, C. Knauf, A. Waget, A.M. Neyrinck, N.M. Delzenne, R. Burcelin, Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008)

    Article  CAS  PubMed  Google Scholar 

  5. A.D. Pradhan, J.E. Manson, N. Rifai, J.E. Buring, P.M. Ridker, C-reactive protein, interleukin 6, and riskof developing type 2 diabetes mellitus. JAMA 286, 327–334 (2001)

    Article  CAS  PubMed  Google Scholar 

  6. A. Chawla, K.D. Nguyen, Y.P. Goh, Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11(11), 738–749 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. G.S. Hotamisligil, Inflammation, metaflammation and immunometabolic disorders. Nature 542(7640), 177–185 (2017)

    Article  CAS  PubMed  Google Scholar 

  8. S.L. Ameres, P.D. Zamore, Diversifying microRNA sequence and function. Nat. Rev. Mol. Cell Biol. 14(8), 475–488 (2013)

    Article  CAS  PubMed  Google Scholar 

  9. Y. Cheng, X. Liu, J. Yang, Y. Lin, D.Z. Xu, Q. Lu, E.A. Deitch, Y. Huo, E.S. Delphin, C. Zhang, MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ. Res. 105(2), 158–166 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. S. Albinsson, W.C. Sessa, Can microRNAs control vascular smooth muscle phenotypic modulation and the response to injury? Physiol. Genom. 43(10), 529–533 (2011)

    Article  CAS  Google Scholar 

  11. F. Sala, J.F. Aranda, N. Rotllan, C.M. Ramirez, B. Aryal, L. Elia, G. Condorelli, A.L. Catapano, C. Fernandez-Hernando, G.D. Norata, MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr-/-mice. Thromb. Haemost. 112(4), 796–802 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  12. M. Boufraqech, L. Zhang, M. Jain, D. Patel, R. Ellis, Y. Xiong, M. He, N. Nilubol, M.J. Merino, E. Kebebew, miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3. Endocr. Relat. Cancer 21(4), 517–531 (2014)

    Article  CAS  PubMed  Google Scholar 

  13. G. Eades, B. Wolfson, Y. Zhang, Q. Li, Y. Yao, Q. Zhou, lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6. Mol. Cancer Res. 13(2), 330–338 (2015)

    Article  CAS  PubMed  Google Scholar 

  14. S. Li, X. Wu, Y. Xu, S. Wu, Z. Li, R. Chen, N. Huang, Z. Zhu, X. Xu, miR-145 suppresses colorectal cancer cell migration and invasion by targeting an ETS-related gene. Oncol. Rep. 36(4), 1917–1926 (2016)

    Article  CAS  PubMed  Google Scholar 

  15. Y. Teng, R. Zhang, C. Liu, L. Zhou, H. Wang, W. Zhuang, Y. Huang, Z. Hong, miR-143 inhibits interleukin-13-induced inflammatory cytokine and mucus production in nasal epithelial cells from allergic rhinitis patients by targeting IL13Ralpha1. Biochem. Biophys. Res. Commun. 457(1), 58–64 (2015)

    Article  CAS  PubMed  Google Scholar 

  16. F. Lovren, Y. Pan, A. Quan, K.K. Singh, P.C. Shukla, N. Gupta, B.M. Steer, A.J. Ingram, M. Gupta, M. Al-Omran, H. Teoh, P.A. Marsden, S. Verma, MicroRNA-145 targeted therapy reduces atherosclerosis. Circulation 126(11Suppl 1), S81–S90 (2012)

    Article  CAS  PubMed  Google Scholar 

  17. M. Yuan, L. Zhang, F. You, J. Zhou, Y. Ma, F. Yang, L. Tao, MiR-145-5p regulates hypoxia-induced inflammatory response and apoptosis in cardiomyocytes by targeting CD40. Mol. Cell Biochem. 431(1-2), 123–131 (2017)

    Article  CAS  PubMed  Google Scholar 

  18. Y. Zhang, Q. Lin, MicroRNA-145 inhibits migration and invasion by down-regulating FSCN1 in lung cancer. Int. J. Clin. Exp. Med 8(6), 8794–8802 (2015)

    CAS  Google Scholar 

  19. S. Lorente-Cebrian, N. Mejhert, A. Kulyte, J. Laurencikiene, G. Astrom, P. Heden, M. Ryden, P. Arner, MicroRNAs regulate human adipocyte lipolysis: effects of miR-145 are linked to TNF-alpha. PLoS One 9(1), e86800 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  20. F. Wen, Y. Yang, D. Jin, J. Sun, X. Yu, Z. Yang, MiRNA-145 is involved in the development of resistin-induced insulin resistance in HepG2 cells. Biochem. Biophys. Res. Commun. 445(2), 517–523 (2014)

    Article  CAS  PubMed  Google Scholar 

  21. Y. Egami, M. Fujii, K. Kawai, Y. Ishikawa, M. Fukuda, N. Araki, Activation-inactivation cycling of Rab35 and ARF6 is required for phagocytosis of zymosan in RAW264 macrophages. J. Immunol. Res 2015, 429439 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  22. T. Hongu, Y. Kanaho, Activation machinery of the small GTPase Arf6. Adv. Biol. Regul. 54, 59–66 (2014)

    Article  CAS  PubMed  Google Scholar 

  23. J.C. Kagan, R. Medzhitov, Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125(5), 943–955 (2006)

    Article  CAS  PubMed  Google Scholar 

  24. T. Van Acker, S. Eyckerman, L. Vande Walle, S. Gerlo, M. Goethals, M. Lamkanfi, C. Bovijn, J. Tavernier, F. Peelman, The small GTPase Arf6 is essential for the Tram/Trif pathway in TLR4 signaling. J. Biol. Chem. 289(3), 1364–1376 (2014)

    Article  PubMed  Google Scholar 

  25. P.D. Cani, J. Amar, M.A. Iglesias, M. Poggi, C. Knauf, D. Bastelica, A.M. Neyrinck, R. Burelin, Metabolic Endotoxemia Initiates Obesity and Insulin Resistance. Diabetes 56(7), 1761–1772 (2007)

    Article  CAS  PubMed  Google Scholar 

  26. A. Muniategui, J. Pey, F.J. Planes, A. Rubio, Joint analysis of miRNA and mRNA expression data. Brief. Bioinform. 14(3), 263–278 (2013)

    Article  CAS  PubMed  Google Scholar 

  27. G.S. Hotamisligil, Inflammation and metabolic disorders. Nature 444(7121), 860–867 (2006)

    Article  CAS  PubMed  Google Scholar 

  28. J.C. McNelis, J.M. Olefsky, Macrophages, immunity, and metabolic disease. Immunity 41(1), 36–48 (2014)

    Article  CAS  PubMed  Google Scholar 

  29. J. Sloan-Lancaster, E. Abu-Raddad, J. Polzer, J.W. Miller, J.C. Scherer, A. De Gaetano, J.K. Berg, W.H. Landschulz, Double-blind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1beta antibody, in patients with type 2 diabetes. Diabetes Care 36(8), 2239–2246 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. P.C. van Poppel, E.J. van Asseldonk, J.J. Holst, T. Vilsboll, M.G. Netea, C.J. Tack, The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance. Diabetes Obes. Metab. 16(12), 1269–1273 (2014)

    Article  PubMed  Google Scholar 

  31. I. Stagakis, G. Bertsias, S. Karvounaris, M. Kavousanaki, D. Virla, A. Raptopoulou, D. Kardassis, D.T. Boumpas, P.I. Sidiropoulos, Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance. Arthritis Res. Ther. 14(3), R141 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. T.L. Stanley, M.V. Zanni, S. Johnsen, S. Rasheed, H. Makimura, H. Lee, V.K. Khor, R.S. Ahima, S.K. Grinspoon, TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J. Clin. Endocrinol. Metab. 96(1), E146–E150 (2011)

    Article  CAS  PubMed  Google Scholar 

  33. J.C. Davies, S. Tamaddon-Jahromi, R. Jannoo, V. Kanamarlapudi, Cytohesin 2/ARF6 regulates preadipocyte migration through the activation of ERK1/2. Biochem. Pharmacol. 92(4), 651–660 (2014)

    Article  CAS  PubMed  Google Scholar 

  34. T. Torii, Y. Miyamoto, A. Sanbe, K. Nishimura, J. Yamauchi, A. Tanoue, Cytohesin-2/ARNO, through its interaction with focal adhesion adaptor protein paxillin, regulates preadipocyte migration via the downstream activation of Arf6. J. Biol. Chem. 285(31), 24270–24281 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. J.C. Davies, S.C. Bain, V. Kanamarlapudi, ADP-ribosylation factor 6 regulates endothelin-1-induced lipolysis in adipocytes. Biochem. Pharmacol. 90(4), 406–413 (2014)

    Article  CAS  PubMed  Google Scholar 

  36. Y. Liu, D. Zhou, N.A. Abumrad, X. Su, ADP-ribosylation factor 6 modulates adrenergic stimulated lipolysis in adipocytes. Am. J. Physiol. Cell Physiol. 298(4), C921–C928 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. J. Li, A.W. Malaby, M. Famulok, H. Sabe, D.G. Lambright, V.W. Hsu, Grp1 plays a key role in linking insulin signaling to glut4 recycling. Dev. Cell 22(6), 1286–1298 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. J. Li, P.J. Peters, M. Bai, J. Dai, E. Bos, T. Kirchhausen, K.V. Kandror, V.W. Hsu, An ACAP1-containing clathrin coat complex for endocytic recycling. J. Cell Biol. 178(3), 453–464 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Natural Science Foundation of China (No.81471057,81270902).

Author information

Authors and Affiliations

  1. Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Rumei Li, Nan Wu, Min He, Naijia Liu, Jinya Huang, Bin Lu, Yehong Yang & Renming Hu

  2. Institute of Endocrinology and Diabetology, Fudan University, Shanghai, 200040, China

    Rumei Li, Nan Wu, Min He, Naijia Liu, Jinya Huang, Bin Lu, Yehong Yang & Renming Hu

  3. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Qiwei Shen & Qiyuan Yao

Authors
  1. Rumei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiwei Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Min He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naijia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinya Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qiyuan Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yehong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Renming Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yehong Yang or Renming Hu.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, R., Shen, Q., Wu, N. et al. MiR-145 improves macrophage-mediated inflammation through targeting Arf6. Endocrine 60, 73–82 (2018). https://doi.org/10.1007/s12020-018-1521-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-018-1521-8

Keywords

Search

Navigation