Abstract
Phagocytes play critical roles in the maintenance of organismal homeostasis and immunity. Central to their role is their ability to take up and process exogenous material via the related processes of phagocytosis and macropinocytosis. The mechanisms and functions underlying macropinocytosis have remained severely understudied relative to phagocytosis. In recent years, however, there has been a renaissance in macropinocytosis research. Phagocytes can engage in various forms of macropinocytosis including an “induced” form and a “constitutive” form. This chapter, however, will focus on constitutive macropinocytosis and its role in the maintenance of immunity. Functions previously attributed to macropinocytosis, including antigen presentation and immune surveillance, will be revisited in light of recent revelations and emerging concepts will be highlighted.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Areschoug T, Gordon S (2009) Scavenger receptors: role in innate immunity and microbial pathogenesis. Cell Microbiol 11:1160–1169. https://doi.org/10.1111/j.1462-5822.2009.01326.x
Bielig H, Rompikuntal PK, Dongre M et al (2011) NOD-like receptor activation by outer membrane vesicles from vibrio cholerae non-O1 non-O139 strains is modulated by the quorum-sensing regulator HapR. Infect Immun 79:1418–1427. https://doi.org/10.1128/IAI.00754-10
Brubaker SW, Bonham KS, Zanoni I, Kagan JC (2015) Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 33:257–290. https://doi.org/10.1146/annurev-immunol-032414-112240
Burgdorf S, Lukacs-Kornek V, Kurts C (2006) The mannose receptor mediates uptake of soluble but not of cell-associated antigen for cross-presentation. J Immunol 176:6770–6776. https://doi.org/10.4049/jimmunol.176.11.6770
Calmette J, Bertrand M, Vétillard M et al (2016) Glucocorticoid-induced leucine zipper protein controls macropinocytosis in dendritic cells. J Immunol 197:4247–4256. https://doi.org/10.4049/jimmunol.1600561
Cañas M-A, Fábrega M-J, Giménez R et al (2018) Outer membrane vesicles from probiotic and commensal Escherichia coli activate NOD1-mediated immune responses in intestinal epithelial cells. Front Microbiol 9. https://doi.org/10.3389/fmicb.2018.00498
Canton J (2018) Macropinocytosis: new insights into its underappreciated role in innate immune cell surveillance. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.02286
Canton J, Neculai D, Grinstein S (2013) Scavenger receptors in homeostasis and immunity. Nat Rev Immunol 13:621–634. https://doi.org/10.1038/nri3515
Canton J, Schlam D, Breuer C et al (2016) Calcium-sensing receptors signal constitutive macropinocytosis and facilitate the uptake of NOD2 ligands in macrophages. Nat Commun 7:1–12. https://doi.org/10.1038/ncomms11284
Champion JA, Walker A, Mitragotri S (2008) Role of particle size in phagocytosis of polymeric microspheres. Pharm Res 25:1815–1821. https://doi.org/10.1007/s11095-008-9562-y
Charpentier JC, Chen D, Lapinski PE et al (2020) Macropinocytosis drives T cell growth by sustaining the activation of mTORC1. Nat Commun 11:1–9. https://doi.org/10.1038/s41467-019-13997-3
Chaturvedi A, Pierce SK (2009) How location governs toll-like receptor signaling. Traffic 10:621–628. https://doi.org/10.1111/j.1600-0854.2009.00899.x
Chefalo PJ, Grandea AG, Kaer LV, Harding CV (2003) Tapasin−/− and TAP1−/− macrophages are deficient in vacuolar alternate class I MHC (MHC-I) processing due to decreased MHC-I stability at phagolysosomal pH. J Immunol 170:5825–5833. https://doi.org/10.4049/jimmunol.170.12.5825
Clayton EL, Cousin MA (2009) The molecular physiology of activity-dependent bulk endocytosis of synaptic vesicles. J Neurochem 111:901–914. https://doi.org/10.1111/j.1471-4159.2009.06384.x
Conigrave AD (2016) The calcium-sensing receptor and the parathyroid: past, present, future. Front Physiol 7. https://doi.org/10.3389/fphys.2016.00563
de la Rosa DA, Canessa CM, Fyfe GK, Zhang P (2000) Structure and regulation of amiloride-sensitive sodium channels. Annu Rev Physiol 62:573–594. https://doi.org/10.1146/annurev.physiol.62.1.573
De Vito P (2006) The sodium/hydrogen exchanger: a possible mediator of immunity. Cell Immunol 240:69–85. https://doi.org/10.1016/j.cellimm.2006.07.001
Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902. https://doi.org/10.1146/annurev.biochem.78.081307.110540
Donaldson JG (2019) Macropinosome formation, maturation and membrane recycling: lessons from clathrin-independent endosomal membrane systems. Philos Trans R Soc B Biol Sci 374:20180148. https://doi.org/10.1098/rstb.2018.0148
Doodnauth SA, Grinstein S, Maxson ME (2019) Constitutive and stimulated macropinocytosis in macrophages: roles in immunity and in the pathogenesis of atherosclerosis. Philos Trans R Soc B Biol Sci 374:20180147. https://doi.org/10.1098/rstb.2018.0147
East L, Isacke CM (2002) The mannose receptor family. Biochim Biophys Acta (BBA) – General Subjects 1572:364–386. https://doi.org/10.1016/S0304-4165(02)00319-7
Freeman SA, Uderhardt S, Saric A et al (2020) Lipid-gated monovalent ion fluxes regulate endocytic traffic and support immune surveillance. Science 367:301–305. https://doi.org/10.1126/science.aaw9544
Garrett WS, Chen L-M, Kroschewski R et al (2000) Developmental control of endocytosis in dendritic cells by Cdc42. Cell 102:325–334. https://doi.org/10.1016/S0092-8674(00)00038-6
Guidi R, Levi L, Rouf SF et al (2013) Salmonella enterica delivers its genotoxin through outer membrane vesicles secreted from infected cells. Cell Microbiol 15:2034–2050. https://doi.org/10.1111/cmi.12172
Hackstein H, Steinschulte C, Fiedel S et al (2007) Sanglifehrin A blocks key dendritic cell functions in vivo and promotes long-term allograft survival together with low-dose CsA. Am J Transplant 7:789–798. https://doi.org/10.1111/j.1600-6143.2006.01729.x
Hackstein H, Taner T, Logar AJ, Thomson AW (2002) Rapamycin inhibits macropinocytosis and mannose receptor–mediated endocytosis by bone marrow–derived dendritic cells. Blood 100:1084–1087. https://doi.org/10.1182/blood.V100.3.1084
Ira T, Jon WK, Jan B (2007) Subendothelial lipoprotein retention as the initiating process in atherosclerosis. Circulation 116:1832–1844. https://doi.org/10.1161/CIRCULATIONAHA.106.676890
Koivusalo M, Welch C, Hayashi H et al (2010) Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling. J Cell Biol 188:547–563. https://doi.org/10.1083/jcb.200908086
Lee G-S, Subramanian N, Kim AI et al (2012) The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca 2+ and cAMP. Nature 492:123–127. https://doi.org/10.1038/nature11588
Lee J, Tattoli I, Wojtal KA et al (2009) pH-dependent internalization of muramyl peptides from early endosomes enables Nod1 and Nod2 signaling. J Biol Chem 284:23818–23829. https://doi.org/10.1074/jbc.M109.033670
Leonard JN, Ghirlando R, Askins J et al (2008) The TLR3 signaling complex forms by cooperative receptor dimerization. PNAS 105:258–263. https://doi.org/10.1073/pnas.0710779105
Lewis WH (1937) Pinocytosis by malignant cells. Am J Cancer 29:666–679. https://doi.org/10.1158/ajc.1937.666
Lim JP, Teasdale RD, Gleeson PA (2012) SNX5 is essential for efficient macropinocytosis and antigen processing in primary macrophages. Biology Open 1:904–914. https://doi.org/10.1242/bio.20122204
Marques PE, Grinstein S, Freeman SA (2017) SnapShot: macropinocytosis. Cell 169:766–766.e1. https://doi.org/10.1016/j.cell.2017.04.031
Masereel B, Pochet L, Laeckmann D (2003) An overview of inhibitors of Na+/H+ exchanger. Eur J Med Chem 38:547–554. https://doi.org/10.1016/S0223-5234(03)00100-4
Moreau HD, Blanch-Mercader C, Attia R et al (2019) Macropinocytosis overcomes directional bias in dendritic cells due to hydraulic resistance and facilitates space exploration. Dev Cell 49:171–188.e5. https://doi.org/10.1016/j.devcel.2019.03.024
Nakamura N, Lill JR, Phung Q et al (2014) Endosomes are specialized platforms for bacterial sensing and NOD2 signalling. Nature 509:240–244. https://doi.org/10.1038/nature13133
Norbury CC, Chambers BJ, Prescott AR et al (1997) Constitutive macropinocytosis allows TAP-dependent major histocompatibility compex class I presentation of exogenous soluble antigen by bone marrow-derived dendritic cells. Eur J Immunol 27:280–288. https://doi.org/10.1002/eji.1830270141
Olszak IT, Poznansky MC, Evans RH et al (2000) Extracellular calcium elicits a chemokinetic response from monocytes in vitro and in vivo. J Clin Invest 105:1299–1305. https://doi.org/10.1172/JCI9799
Orlowski J, Grinstein S (2011) Na+/H+ exchangers. In: Comprehensive physiology. American Cancer Society, pp 2083–2100
Prentice-Mott HV, Chang C-H, Mahadevan L et al (2013) Biased migration of confined neutrophil-like cells in asymmetric hydraulic environments. Proc Natl Acad Sci U S A 110:21006–21011. https://doi.org/10.1073/pnas.1317441110
Racoosin EL, Swanson JA (1993) Macropinosome maturation and fusion with tubular lysosomes in macrophages. J Cell Biol 121:1011–1020. https://doi.org/10.1083/jcb.121.5.1011
Redka DS, Gütschow M, Grinstein S, Canton J (2018) Differential ability of proinflammatory and anti-inflammatory macrophages to perform macropinocytosis. MBoC 29:53–65. https://doi.org/10.1091/mbc.E17-06-0419
Roier S, Zingl FG, Cakar F et al (2016) A novel mechanism for the biogenesis of outer membrane vesicles in Gram-negative bacteria. Nat Commun 7:1–13. https://doi.org/10.1038/ncomms10515
Rosales-Reyes R, Pérez-López A, Sánchez-Gómez C et al (2012) Salmonella infects B cells by macropinocytosis and formation of spacious phagosomes but does not induce pyroptosis in favor of its survival. Microb Pathog 52:367–374. https://doi.org/10.1016/j.micpath.2012.03.007
Sallusto F, Cella M, Danieli C, Lanzavecchia A (1995) Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J Exp Med 182:389–400. https://doi.org/10.1084/jem.182.2.389
Sarkar K, Kruhlak MJ, Erlandsen SL, Shaw S (2005) Selective inhibition by rottlerin of macropinocytosis in monocyte-derived dendritic cells. Immunology 116:513–524. https://doi.org/10.1111/j.1365-2567.2005.02253.x
Schlam D, Bagshaw RD, Freeman SA et al (2015) Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins. Nat Commun 6:1–12. https://doi.org/10.1038/ncomms9623
Schlam D, Canton J (2016) Every day I’m rufflin’: calcium sensing and actin dynamics in the growth factor-independent membrane ruffling of professional phagocytes. Small GTPases 8:65–70. https://doi.org/10.1080/21541248.2016.1197873
Singla B, Ghoshal P, Lin H et al (2018) PKCδ-mediated Nox2 activation promotes fluid-phase pinocytosis of antigens by immature dendritic cells. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.00537
Sorvillo N, Pos W, van den Berg LM et al (2012) The macrophage mannose receptor promotes uptake of ADAMTS13 by dendritic cells. Blood 119:3828–3835. https://doi.org/10.1182/blood-2011-09-377754
Steinman RM, Brodie SE, Cohn ZA (1976) Membrane flow during pinocytosis. A stereologic analysis. J Cell Biol 68:665–687. https://doi.org/10.1083/jcb.68.3.665
Swanson JA, King JS (2019) The breadth of macropinocytosis research. Philos Trans R Soc B Biol Sci 374:20180146. https://doi.org/10.1098/rstb.2018.0146
Uderhardt S, Martins AJ, Tsang JS et al (2019) Resident macrophages cloak tissue microlesions to prevent neutrophil-driven inflammatory damage. Cell 177:541–555.e17. https://doi.org/10.1016/j.cell.2019.02.028
Vanaja SK, Russo AJ, Behl B et al (2016) Bacterial outer membrane vesicles mediate cytosolic localization of LPS and caspase-11 activation. Cell 165:1106–1119. https://doi.org/10.1016/j.cell.2016.04.015
von Delwig A, Hilkens CM, Altmann DM et al (2006) Inhibition of macropinocytosis blocks antigen presentation of type II collagen in vitro and in vivoin HLA-DR1 transgenic mice. Arthritis Res Therapy 8:R93. https://doi.org/10.1186/ar1964
West MA, Prescott AR, Eskelinen E-L et al (2000) Rac is required for constitutive macropinocytosis by dendritic cells but does not control its downregulation. Curr Biol 10:839–848. https://doi.org/10.1016/S0960-9822(00)00595-9
West MA, Wallin RPA, Matthews SP et al (2004) Enhanced dendritic cell antigen capture via toll-like receptor-induced actin remodeling. Science 305:1153–1157. https://doi.org/10.1126/science.1099153
Yoshida S, Pacitto R, Sesi C et al (2018) Dorsal ruffles enhance activation of Akt by growth factors. J Cell Sci 131. https://doi.org/10.1242/jcs.220517
Zindel J, Kubes P (2020) DAMPs, PAMPs, and LAMPs in immunity and sterile inflammation. Annu Rev Pathol: Mechanisms Disease 15:493–518. https://doi.org/10.1146/annurev-pathmechdis-012419-032847
Acknowledgments
I would like to thank the editors for their critical reading of this manuscript and Elizabeth Tamas and Gerone Gonzales for their help with the figures.
Author Contributions
The author confirms being the sole contributor to this work and has approved it for publication.
Conflict of Interest
The author declares that the manuscript was prepared in the absence of any commercial or financial relationships that may be construed as a potential conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Canton, J. (2022). Macropinocytosis in Phagocyte Function and Immunity. In: Commisso, C. (eds) Macropinocytosis. Subcellular Biochemistry, vol 98. Springer, Cham. https://doi.org/10.1007/978-3-030-94004-1_6
Download citation
DOI: https://doi.org/10.1007/978-3-030-94004-1_6
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-94003-4
Online ISBN: 978-3-030-94004-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)