Immunologic Research

, Volume 67, Issue 1, pp 1–11 | Cite as

Macrophage phenotype bioengineered by magnetic, genetic, or pharmacologic interference

  • Jarek WosikEmail author
  • Martha Suarez-Villagran
  • John H. MillerJr
  • Rafik M. Ghobrial
  • Malgorzata KlocEmail author


In all eukaryotes, the cell shape depends on the actin filament cytoskeleton, which is regulated by the small GTPase RhoA. It is well known that the cell shape determines cell function and behavior. Inversely, any change in the cell behavior and/or function reverberates at the cell shape. In this review, we describe how mechanical/magnetic, genetic, or pharmacologic interference with the actin cytoskeleton enforces changes in cell shape and function and how such techniques can be used to control the phenotype and functions of immune cells such as macrophages and to develop novel anti-cancer and anti-rejection clinical therapies.


Macrophage RhoA Actin Magnetic field Transplantation Cancer 



The authors gratefully acknowledge the support from the William and Ella Owens Medical Research Foundation, the William Stamps Farish Fund, and the State of Texas through the Texas Center for Superconductivity at the University of Houston.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Lee M, Vasioukhin V. Cell polarity and cancer—cell and tissue polarity as a non-canonical tumor suppressor. J Cell Sci. 2008;121(Pt 8):1141–50. Google Scholar
  2. 2.
    Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327(5966):656–61. Scholar
  3. 3.
    Kloc M, Li X, Ghobrial R. Are macrophages responsible for cancer metastasis? J Immuno Biol. 2016;1:103. Google Scholar
  4. 4.
    Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11(11):723–37. Scholar
  5. 5.
    Kloc M, Ghobrial RM. Chronic allograft rejection: a significant hurdle to transplant success. Burns Trauma. 2014;2(1):3–10. Scholar
  6. 6.
    Kloc M, Li X, Ghobrial RM. RhoA cytoskeletal pathway to transplantation. J Immun Clincal Res. 2014;2:1012–6.Google Scholar
  7. 7.
    Liu Y, Kloc M, Li XC. Macrophages as effectors of acute and chronic allograft injury. Curr Transplant Rep. 2016;3(4):303–12. Scholar
  8. 8.
    Kaul AM, Goparaju S, Dvorina N, Iida S, Keslar KS, de la Motte CA, et al. Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants. Am J Transplant. 2015;15(2):333–45. Scholar
  9. 9.
    Hettinger J, Richards DM, Hansson J, Barra MM, Joschko AC, Krijgsveld J, et al. Origin of monocytes and macrophages in a committed progenitor. Nat Immunol. 2013;14(8):821–30. Scholar
  10. 10.
    Liu Y, Minze LJ, Mumma L, Li XC, Ghobrial RM, Kloc M. Mouse macrophage polarity and ROCK1 activity depend on RhoA and non-apoptotic caspase 3. Exp Cell Res. 2016;341(2):225–36. Scholar
  11. 11.
    Liu Y, Tejpal N, You J, Li XC, Ghobrial RM, Kloc M. ROCK inhibition impedes macrophage polarity and functions. Cell Immunol. 2016;300:54–62. Scholar
  12. 12.
    Liu Y, Chen W, Minze LJ, Kubiak JZ, Li XC, Ghobrial RM, et al. Dissonant response of M0/M2 and M1 bone-marrow-derived macrophages to RhoA pathway interference. Cell Tissue Res. 2016;366:707–20. Scholar
  13. 13.
    Liu Y, Kubiak JZ, Li XC, Ghobrial RM, Kloc M. Macrophages and RhoA pathway in transplanted organs. Results Probl Cell Differ. 2017;62:365–76. Google Scholar
  14. 14.
    McWhorter FY, Wang T, Nguyen P, Chung T, Liu WF. Modulation of macrophage phenotype by cell shape. Proc Natl Acad Sci U S A. 2013;110(43):17253–8. Scholar
  15. 15.
    Artemenko Y, Axiotakis L Jr, Borleis J, Iglesias PA, Devreotes PN. Chemical and mechanical stimuli act on common signal transduction and cytoskeletal networks. Proc Natl Acad Sci U S A. 2016;113(47):E7500–E9. Google Scholar
  16. 16.
    Lin BH, Tsai MH, Lii CK, Wang TS. IP3 and calcium signaling involved in the reorganization of the actin cytoskeleton and cell rounding induced by cigarette smoke extract in human endothelial cells. Environ Toxicol. 2016;31(11):1293–306. Scholar
  17. 17.
    Cunniff B, McKenzie AJ, Heintz NH, Howe AK. AMPK activity regulates trafficking of mitochondria to the leading edge during cell migration and matrix invasion. Mol Biol Cell. 2016;27(17):2662–74. Scholar
  18. 18.
    Mehta MM, Weinberg SE, Chandel NS. Mitochondrial control of immunity: beyond ATP. Nat Rev Immunol. 2017;17(10):608–20. Scholar
  19. 19.
    Schuler MH, Lewandowska A, Caprio GD, Skillern W, Upadhyayula S, Kirchhausen T, et al. Miro1-mediated mitochondrial positioning shapes intracellular energy gradients required for cell migration. Mol Biol Cell. 2017;28(16):2159–69. Scholar
  20. 20.
    Wheeler AP, Ridley AJ. Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility. Exp Cell Res. 2004;301(1):43–9. Scholar
  21. 21.
    Bos N, Zimmerman A, Olson J, Yew J, Yerkie J, Dahl E, et al. From shared databases to communities of practice: a taxonomy of collaboratories. J Computer-Mediated Comm. 2007;12(2):652–72. Scholar
  22. 22.
    Cherfils J, Zeghouf M. Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev. 2013;93(1):269–309. Scholar
  23. 23.
    Dubash AD, Wennerberg K, Garcia-Mata R, Menold MM, Arthur WT, Burridge K. A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin. J Cell Sci. 2007;120(Pt 22):3989–98. Google Scholar
  24. 24.
    Shang X, Marchioni F, Sipes N, Evelyn CR, Jerabek-Willemsen M, Duhr S, et al. Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases. Chem Biol. 2012;19(6):699–710. Scholar
  25. 25.
    Shang X, Marchioni F, Evelyn CR, Sipes N, Zhou X, Seibel W, et al. Small-molecule inhibitors targeting G-protein-coupled Rho guanine nucleotide exchange factors. Proc Natl Acad Sci U S A. 2013;110(8):3155–60. Scholar
  26. 26.
    Goode BL, Eskin JA, Wendland B. Actin and endocytosis in budding yeast. Genetics. 2015;199(2):315–58. Scholar
  27. 27.
    Egea G, Serra-Peinado C, Gavilan MP, Rios RM. Cytoskeleton and Golgi-apparatus interactions: a two-way road of function and structure. Cell Health Cytosk. 2015:37.
  28. 28.
    Marra P, Salvatore L, Mironov A Jr, Di Campli A, Di Tullio G, Trucco A, et al. The biogenesis of the Golgi ribbon: the roles of membrane input from the ER and of GM130. Mol Biol Cell. 2007;18(5):1595–608. Scholar
  29. 29.
    Maxfield FR, McGraw TE. Endocytic recycling. Nat Rev Mol Cell Biol. 2004;5(2):121–32. Scholar
  30. 30.
    Prosser DC, Wendland B. Conserved roles for yeast Rho1 and mammalian RhoA GTPases in clathrin-independent endocytosis. Small GTPases. 2012;3(4):229–35. Scholar
  31. 31.
    Rossanese O, Reinke C, Bevis B, Hammond A, Sears I, O'Connor J, et al. A role for actin, Cdc1p, and Myo2p in the inheritance of late Golgi elements in Saccharomyces cerevisiae. J Cell Biol. 2001;153(1):47–62.Google Scholar
  32. 32.
    Zilberman Y, Alieva NO, Miserey-Lenkei S, Lichtenstein A, Kam Z, Sabanay H, et al. Involvement of the Rho-mDia1 pathway in the regulation of Golgi complex architecture and dynamics. Mol Biol Cell. 2011;22(16):2900–11. Scholar
  33. 33.
    Meunier FA, Gutierrez LM. Captivating new roles of F-actin cortex in exocytosis and bulk endocytosis in neurosecretory cells. Trends Neurosci. 2016;39(9):605–13. Scholar
  34. 34.
    Mori TTK, Naito M, Kodama T, Hakamata H, Sakai M, Miyazaki A, et al. Endocytic pathway of scavenger receptors via trans-Golgi system in bovine alveolar macrophages. Lab Investig. 1994;71(3):409–16.Google Scholar
  35. 35.
    Liu Y, Chen W, Wu C, Minze LJ, Kubiak JZ, Li XC et al. Macrophage/monocyte-specific deletion of Ras homolog gene family member A (RhoA) downregulates fractalkine receptor and inhibits chronic rejection of mouse cardiac allografts. J Heart Lung Transpl. 2016:30292–3.
  36. 36.
    Chen W, Zhao Y, Li XC, Kubiak JZ, Ghobrial RM, Kloc M. Rho-specific guanine nucleotide exchange factors (Rho-GEFs) inhibition affects macrophage phenotype and disrupts Golgi complex. Int J Biochem Cell Biol. 2017;93:12–24. Scholar
  37. 37.
    Porat-Shliom N, Weigert R, Donaldson JG. Endosomes derived from clathrin-independent endocytosis serve as precursors for endothelial lumen formation. PLoS One. 2013;8(11):e81987. Scholar
  38. 38.
    Lee K, Kim EH, Oh N, Tuan NA, Bae NH, Lee SJ, et al. Contribution of actin filaments and microtubules to cell elongation and alignment depends on the grating depth of microgratings. J Nanobiotechnology. 2016;14(1):35. Google Scholar
  39. 39.
    Lee CH, Kim YJ, Jang JH, Park JW. Modulating macrophage polarization with divalent cations in nanostructured titanium implant surfaces. Nanotechnology. 2016;27(8):085101. Scholar
  40. 40.
    Wang T, Luu TU, Chen A, Khine M, Liu WF. Topographical modulation of macrophage phenotype by shrink-film multi-scale wrinkles. Biomater Sci. 2016;4(6):948–52. Scholar
  41. 41.
    Wosik J, Chen W, Qin K, Ghobrial RM, Kubiak JZ, Kloc M. Magnetic field changes macrophage phenotype. Biophys J. 2018;114(8):2001–13. Scholar
  42. 42.
  43. 43.
    Eguchi Y, Ueno S, Kaito C, Sekimizu K, Shiokawa K. Cleavage and survival of Xenopus embryos exposed to 8 T static magnetic fields in a rotating clinostat. Bioelectromagnetics. 2006;27(4):307–13. Scholar
  44. 44.
    Denegre JM, Valles JM Jr, Lin K, Jordan WB, Mowry KL. Cleavage planes in frog eggs are altered by strong magnetic fields. Proc Natl Acad Sci U S A. 1998;95(25):14729–32.Google Scholar
  45. 45.
    Kauffmann P, Ith A, O'Brien D, Gaude V, Boue F, Combe S, et al. Diamagnetically trapped arrays of living cells above micromagnets. Lab Chip. 2011;11(18):3153–61. Scholar
  46. 46.
    Gassner AL, Abonnenc M, Chen HX, Morandini J, Josserand J, Rossier JS, et al. Magnetic forces produced by rectangular permanent magnets in static microsystems. Lab Chip. 2009;9(16):2356–63. Scholar
  47. 47.
    Zablotskii V, Pastor JMn, Larumbe S, Pérez-Landazábal JI, Recarte V, Gómez-Polo C et al. High-field gradient permanent micromagnets for targeted drug delivery with magnetic nanoparticles. 2010:152–157. doi:
  48. 48.
    Gijs MA, Lacharme F, Lehmann U. Microfluidic applications of magnetic particles for biological analysis and catalysis. Chem Rev. 2010;110(3):1518–63. Scholar
  49. 49.
    Ghibaudo M, Trichet L, Le Digabel J, Richert A, Hersen P, Ladoux B. Substrate topography induces a crossover from 2D to 3D behavior in fibroblast migration. Biophys J. 2009;97(1):357–68. Scholar
  50. 50.
    Ladoux B, Nicolas A. Physically based principles of cell adhesion mechanosensitivity in tissues. Rep Prog Phys. 2012;75(11):116601. Scholar
  51. 51.
    Bryan AK, Hecht VC, Shen W, Payer K, Grover WH, Manalis SR. Measuring single cell mass, volume, and density with dual suspended microchannel resonators. Lab Chip. 2014;14(3):569–76. Scholar
  52. 52.
    Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(1):33–8. Scholar
  53. 53.
    Omelchenko T, Vasiliev JM, Gelfand IM, Feder HH, Bonder EM. Rho-dependent formation of epithelial “leader” cells during wound healing. Proc Natl Acad Sci U S A. 2003;100(19):10788–93. Scholar
  54. 54.
    Gov NS. Collective cell migration patterns: follow the leader. Proc Natl Acad Sci U S A. 2007;104(41):15970–1. Scholar
  55. 55.
    Qian A-R, Gao X, Zhang W, Li J-B, Wang Y, Di S-M, et al. Large gradient high magnetic fields affect osteoblast ultrastructure and function by disrupting collagen I or fibronectin/αβ1 integrin. PLoS One. 2013;8(1):e51036.Google Scholar
  56. 56.
    Chionna A, Dwikat M, Panzarini E, Tenuzzo B, Carla EC, Verri T, et al. Cell shape and plasma membrane alterations after static magnetic fields exposure. Eur J Histochem. 2003;47(4):299–308.Google Scholar
  57. 57.
    Winkleman A, Gudiksen KL, Ryan D, Whitesides GM, Greenfield D, Prentiss M. A magnetic trap for living cells suspended in a paramagnetic buffer. Appl Phys Lett. 2004;85(12):2411–3. Scholar
  58. 58.
    Shi D, Meng R, Deng W, Ding W, Zheng Q, Yuan W, et al. Effects of microgravity modeled by large gradient high magnetic field on the osteogenic initiation of human mesenchymal stem cells. Stem Cell Rev Rep. 2010;6(4):567–78.Google Scholar
  59. 59.
    Beaugnon E, Tournier R. Levitation of organic materials. Nature. 1991;349(6309):470.Google Scholar
  60. 60.
    Kuznetsov OA, Hasenstein KH. Intracellular magnetophoresis of amyloplasts and induction of root curvature. Planta. 1996;198(1):87–94.Google Scholar
  61. 61.
    Yamaguchi M, Tanimoto Y. Magneto-science: magnetic field effects on materials: fundamentals and applications, Springer Series in Materials Science, Volume 89 ISBN 978-3-540-37061-1 Kodansha Ltd and Springer-Verlag Berlin Heidelberg, 2006. 2006;1.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Electrical and Computer Engineering DepartmentUniversity of HoustonHoustonUSA
  2. 2.Texas Center for SuperconductivityUniversity of HoustonHoustonUSA
  3. 3.Physics DepartmentUniversity of HoustonHoustonUSA
  4. 4.The Houston Methodist Research InstituteHoustonUSA
  5. 5.Department of SurgeryThe Houston Methodist HospitalHoustonUSA
  6. 6.M.D. Anderson Cancer Center, Department of GeneticsThe University of TexasHoustonUSA

Personalised recommendations