Chapter 7 : Myeloid Cell Turnover and Clearance

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Myeloid Cell Turnover and Clearance, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819194/9781555819187_Chap07-1.gif /docserver/preview/fulltext/10.1128/9781555819194/9781555819187_Chap07-2.gif


Few, if any, individual cells survive throughout the life of the animal, an observation that sets up the critical concepts of cell life span, turnover, and removal and maintenance of homeostatic cell numbers. These issues are of special interest for understanding the properties of the myeloid cell lineage, which includes cells such as neutrophils, which may exhibit in the normal naive adult mammal the shortest life span of all but yet are maintained in relatively constant numbers within the circulation. However, our understanding of the underlying mechanisms for myeloid cell maintenance and removal is still substantially limited and also requires reexamination in light of new ideas about the ontogeny, characterization, and distribution of the myeloid cells in general. Accordingly, this essay will focus on the concepts and questions that, we argue, are in need of exploration, rather than providing a detailed review of what is a huge literature. By focusing on four of the myeloid-lineage cell types (neutrophils, monocytes, macrophages, and dendritic cells [DCs]), we will also be able to bring to the fore many of the key issues that characterize this set of questions.

Citation: Janssen W, Bratton D, Jakubzick C, Henson P. 2017. Myeloid Cell Turnover and Clearance, p 99-115. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0005-2015
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

Mechanisms for recognition and uptake of apoptotic cells. Changes on the apoptotic cell surface, including exposure of PS and other normally internally located molecules, are recognized by surface receptors on the phagocyte, leading to tethering of the apoptotic cell and transduction of uptake signals. Bridge molecules (opsonins) in the environment or produced by the phagocyte may also recognize the apoptotic surface changes and also a different set of receptors on the phagocyte to initiate tethering and/or signaling. These processes are significantly redundant and also highly regulated by enhancing or inhibitory stimuli. Viable cells may also avoid removal by expressing “don’t eat me” stimuli that block the recognition and/or uptake processes.

Citation: Janssen W, Bratton D, Jakubzick C, Henson P. 2017. Myeloid Cell Turnover and Clearance, p 99-115. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0005-2015
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

Uptake of apoptotic neutrophils by a macrophage in the alveolar air space during resolution of inflammation in the lung.

Citation: Janssen W, Bratton D, Jakubzick C, Henson P. 2017. Myeloid Cell Turnover and Clearance, p 99-115. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0005-2015
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

Time course of a standardized acute inflammatory response in the lung, showing accumulation and removal of neutrophils and monocyte/macrophages. The resident alveolar macrophages persist throughout the inflammation and do not substantially change in numbers. Some of the recruited Ly6C monocytes mature into macrophages (and DCs), and some remain as monocytes. The macrophages undergo a variety of programming changes during the course of the inflammation, participating in first its initiation and then its resolution. The monocytes and macrophages are cleared as the inflammation wanes, mostly by undergoing PCD and engulfment, though some of the monocytes migrate to the local lymph nodes and, at this site, some of the cells may also be cleared physically up the airways by the mucociliary escalator.

Citation: Janssen W, Bratton D, Jakubzick C, Henson P. 2017. Myeloid Cell Turnover and Clearance, p 99-115. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0005-2015
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Fadok VA,, Voelker DR,, Campbell PA,, Cohen JJ,, Bratton DL,, Henson PM . 1992. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148 : 2207 2216.
2. Takatsu H,, Tanaka G,, Segawa K,, Suzuki J,, Nagata S,, Nakayama K,, Shin HW . 2014. Phospholipid flippase activities and substrate specificities of human type IV P-type ATPases localized to the plasma membrane. J Biol Chem 289 : 33543 33556.
3. Suzuki J,, Nagata S . 2014. Phospholipid scrambling on the plasma membrane. Methods Enzymol 544 : 381 393.
4. Segawa K,, Nagata S . 2015. An apoptotic ‘eat me’ signal: phosphatidylserine exposure. Trends Cell Biol 25 : 639 650.
5. Gardai SJ,, Bratton DL,, Ogden CA,, Henson PM . 2006. Recognition ligands on apoptotic cells: a perspective. J Leukoc Biol 79 : 896 903.
6. Poon IK,, Lucas CD,, Rossi AG,, Ravichandran KS . 2014. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol 14 : 166 180.
7. Ravichandran KS . 2011. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35 : 445 455.
8. Yoshida H,, Kawane K,, Koike M,, Mori Y,, Uchiyama Y,, Nagata S . 2005. Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells. Nature 437 : 754 758.
9. Birge RB,, Ucker DS . 2008. Innate apoptotic immunity: the calming touch of death. Cell Death Differ 15 : 1096 1102.
10. D’mello V,, Birge RB . 2010. Apoptosis: conserved roles for integrins in clearance. Curr Biol 20 : R324 R327.
11. Elliott MR,, Ravichandran KS . 2010. Clearance of apoptotic cells: implications in health and disease. J Cell Biol 189 : 1059 1070.
12. deCathelineau AM,, Henson PM . 2003. The final step in programmed cell death: phagocytes carry apoptotic cells to the grave. Essays Biochem 39 : 105 117.
13. Hoffmann PR,, deCathelineau AM,, Ogden CA,, Leverrier Y,, Bratton DL,, Daleke DL,, Ridley AJ,, Fadok VA,, Henson PM . 2001. Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J Cell Biol 155 : 649 659.
14. Mazzoni F,, Safa H,, Finnemann SC . 2014. Understanding photoreceptor outer segment phagocytosis: use and utility of RPE cells in culture. Exp Eye Res 126 : 51 60.
15. Bratton DL,, Henson PM . 2011. Neutrophil clearance: when the party is over, clean-up begins. Trends Immunol 32 : 350 357.
16. Erwig LP,, Henson PM . 2007. Immunological consequences of apoptotic cell phagocytosis. Am J Pathol 171 : 2 8.
17. Scott RS,, McMahon EJ,, Pop SM,, Reap EA,, Caricchio R,, Cohen PL,, Earp HS,, Matsushima GK . 2001. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411 : 207 211.
18. Pillay J,, den Braber I,, Vrisekoop N,, Kwast LM,, de Boer RJ,, Borghans JA,, Tesselaar K,, Koenderman L . 2010. In vivo labeling with 2H 2O reveals a human neutrophil lifespan of 5.4 days. Blood 116 : 625 627.
19. Summers C,, Rankin SM,, Condliffe AM,, Singh N,, Peters AM,, Chilvers ER . 2010. Neutrophil kinetics in health and disease. Trends Immunol 31 : 318 324.
20. Stark MA,, Huo Y,, Burcin TL,, Morris MA,, Olson TS,, Ley K . 2005. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22 : 285 294.
21. Casanova-Acebes M,, Pitaval C,, Weiss LA,, Nombela-Arrieta C,, Chèvre R,, A-González N,, Kunisaki Y,, Zhang D,, van Rooijen N,, Silberstein LE,, Weber C,, Nagasawa T,, Frenette PS,, Castrillo A,, Hidalgo A . 2013. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153 : 1025 1035.
22. Furze RC,, Rankin SM . 2008. The role of the bone marrow in neutrophil clearance under homeostatic conditions in the mouse. FASEB J 22 : 3111 3119.
23. A-Gonzalez N,, Bensinger SJ,, Hong C,, Beceiro S,, Bradley MN,, Zelcer N,, Deniz J,, Ramirez C,, Díaz M,, Gallardo G,, de Galarreta CR,, Salazar J,, Lopez F,, Edwards P,, Parks J,, Andujar M,, Tontonoz P,, Castrillo A . 2009. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31 : 245 258.
24. Majai G,, Sarang Z,, Csomós K,, Zahuczky G,, Fésüs L . 2007. PPARγ-dependent regulation of human macrophages in phagocytosis of apoptotic cells. Eur J Immunol 37 : 1343 1354.
25. Mukundan L,, Odegaard JI,, Morel CR,, Heredia JE,, Mwangi JW,, Ricardo-Gonzalez RR,, Goh YP,, Eagle AR,, Dunn SE,, Awakuni JU,, Nguyen KD,, Steinman L,, Michie SA,, Chawla A . 2009. PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med 15 : 1266 1272.
26. Hong C,, Kidani Y,, A-Gonzalez N,, Phung T,, Ito A,, Rong X,, Ericson K,, Mikkola H,, Beaven SW,, Miller LS,, Shao WH,, Cohen PL,, Castrillo A,, Tontonoz P,, Bensinger SJ . 2012. Coordinate regulation of neutrophil homeostasis by liver X receptors in mice. J Clin Invest 122 : 337 347.
27. Gordy C,, Pua H,, Sempowski GD,, He YW . 2011. Regulation of steady-state neutrophil homeostasis by macrophages. Blood 117 : 618 629.
28. Auffray C,, Fogg D,, Garfa M,, Elain G,, Join-Lambert O,, Kayal S,, Sarnacki S,, Cumano A,, Lauvau G,, Geissmann F . 2007. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317 : 666 670.
29. Carlin LM,, Stamatiades EG,, Auffray C,, Hanna RN,, Glover L,, Vizcay-Barrena G,, Hedrick CC,, Cook HT,, Diebold S,, Geissmann F . 2013. Nr4a1-dependent Ly6C low monocytes monitor endothelial cells and orchestrate their disposal. Cell 153 : 362 375.
30. Guilliams M,, Ginhoux F,, Jakubzick C,, Naik SH,, Onai N,, Schraml BU,, Segura E,, Tussiwand R,, Yona S . 2014. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol 14 : 571 578.
31. Yona S,, Kim KW,, Wolf Y,, Mildner A,, Varol D,, Breker M,, Strauss-Ayali D,, Viukov S,, Guilliams M,, Misharin A,, Hume DA,, Perlman H,, Malissen B,, Zelzer E,, Jung S . 2013. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38 : 79 91.
32. Hettinger J,, Richards DM,, Hansson J,, Barra MM,, Joschko AC,, Krijgsveld J,, Feuerer M . 2013. Origin of monocytes and macrophages in a committed progenitor. Nat Immunol 14 : 821 830.
33. Jakubzick C,, Gautier EL,, Gibbings SL,, Sojka DK,, Schlitzer A,, Johnson TE,, Ivanov S,, Duan Q,, Bala S,, Condon T,, van Rooijen N,, Grainger JR,, Belkaid Y,, Ma’ayan A,, Riches DW,, Yokoyama WM,, Ginhoux F,, Henson PM,, Randolph GJ . 2013. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39 : 599 610.
34. Kamath AT,, Henri S,, Battye F,, Tough DF,, Shortman K . 2002. Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood 100 : 1734 1741.
35. Liu K,, Waskow C,, Liu X,, Yao K,, Hoh J,, Nussenzweig M . 2007. Origin of dendritic cells in peripheral lymphoid organs of mice. Nat Immunol 8 : 578 583.
36. Serbina NV,, Salazar-Mather TP,, Biron CA,, Kuziel WA,, Pamer EG . 2003. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19 : 59 70.
37. Greter M,, Helft J,, Chow A,, Hashimoto D,, Mortha A,, Agudo-Cantero J,, Bogunovic M,, Gautier EL,, Miller J,, Leboeuf M,, Lu G,, Aloman C,, Brown BD,, Pollard JW,, Xiong H,, Randolph GJ,, Chipuk JE,, Frenette PS,, Merad M . 2012. GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 36 : 1031 1046.
38. Chen M,, Huang L,, Shabier Z,, Wang J . 2007. Regulation of the lifespan in dendritic cell subsets. Mol Immunol 44 : 2558 2565.
39. Woodfin A,, Voisin MB,, Beyrau M,, Colom B,, Caille D,, Diapouli FM,, Nash GB,, Chavakis T,, Albelda SM,, Rainger GE,, Meda P,, Imhof BA,, Nourshargh S . 2011. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo . Nat Immunol 12 : 761 769.
40. Chtanova T,, Schaeffer M,, Han SJ,, van Dooren GG,, Nollmann M,, Herzmark P,, Chan SW,, Satija H,, Camfield K,, Aaron H,, Striepen B,, Robey EA . 2008. Dynamics of neutrophil migration in lymph nodes during infection. Immunity 29 : 487 496.
41. McCubbrey AL,, Curtis JL . 2013. Efferocytosis and lung disease. Chest 143 : 1750 1757.
42. Scott DA,, Krauss J . 2012. Neutrophils in periodontal inflammation. Front Oral Biol 15 : 56 83.
43. Geering B,, Stoeckle C,, Conus S,, Simon HU . 2013. Living and dying for inflammation: neutrophils, eosinophils, basophils. Trends Immunol 34 : 398 409.
44. Mihalache CC,, Simon HU . 2012. Autophagy regulation in macrophages and neutrophils. Exp Cell Res 318 : 1187 1192.
45. Brinkmann V,, Reichard U,, Goosmann C,, Fauler B,, Uhlemann Y,, Weiss DS,, Weinrauch Y,, Zychlinsky A . 2004. Neutrophil extracellular traps kill bacteria. Science 303 : 1532 1535.
46. Yipp BG,, Petri B,, Salina D,, Jenne CN,, Scott BN,, Zbytnuik LD,, Pittman K,, Asaduzzaman M,, Wu K,, Meijndert HC,, Malawista SE,, de Boisfleury Chevance A,, Zhang K,, Conly J,, Kubes P . 2012. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo . Nat Med 18 : 1386 1393.
47. Frasch SC,, Berry KZ,, Fernandez-Boyanapalli R,, Jin HS,, Leslie C,, Henson PM,, Murphy RC,, Bratton DL . 2008. NADPH oxidase-dependent generation of lysophosphatidylserine enhances clearance of activated and dying neutrophils via G2A. J Biol Chem 283 : 33736 33749.
48. Frasch SC,, Fernandez-Boyanapalli RF,, Berry KA,, Murphy RC,, Leslie CC,, Nick JA,, Henson PM,, Bratton DL . 2013. Neutrophils regulate tissue neutrophilia in inflammation via the oxidant-modified lipid lysophosphatidylserine. J Biol Chem 288 : 4583 4593.
49. Frasch SC,, Fernandez-Boyanapalli RF,, Berry KZ,, Leslie CC,, Bonventre JV,, Murphy RC,, Henson PM,, Bratton DL . 2011. Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity. J Biol Chem 286 : 12108 12122.
50. Schulz C,, Gomez Perdiguero E,, Chorro L,, Szabo-Rogers H,, Cagnard N,, Kierdorf K,, Prinz M,, Wu B,, Jacobsen SE,, Pollard JW,, Frampton J,, Liu KJ,, Geissmann F . 2012. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336 : 86 90.
51. Scott CL,, Henri S,, Guilliams M . 2014. Mononuclear phagocytes of the intestine, the skin, and the lung. Immunol Rev 262 : 9 24.
52. Janssen WJ,, Barthel L,, Muldrow A,, Oberley-Deegan RE,, Kearns MT,, Jakubzick C,, Henson PM . 2011. Fas determines differential fates of resident and recruited macrophages during resolution of acute lung injury. Am J Respir Crit Care Med 184 : 547 560.
53. Bain CC,, Bravo-Blas A,, Scott CL,, Gomez Perdiguero E,, Geissmann F,, Henri S,, Malissen B,, Osborne LC,, Artis D,, Mowat AM . 2014. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol 15 : 929 937.
54. Murphy J,, Summer R,, Wilson AA,, Kotton DN,, Fine A . 2008. The prolonged life-span of alveolar macrophages. Am J Respir Cell Mol Biol 38 : 380 385.
55. Guth AM,, Janssen WJ,, Bosio CM,, Crouch EC,, Henson PM,, Dow SW . 2009. Lung environment determines unique phenotype of alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 296 : L936 L946.
56. Jenkins SJ,, Ruckerl D,, Cook PC,, Jones LH,, Finkelman FD,, van Rooijen N,, MacDonald AS,, Allen JE . 2011. Local macrophage proliferation, rather than recruitment from the blood, is a signature of T H2 inflammation. Science 332 : 1284 1288.
57. Bellingan GJ,, Caldwell H,, Howie SE,, Dransfield I,, Haslett C . 1996. In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes. J Immunol 157 : 2577 2585.
58. Cao C,, Lawrence DA,, Strickland DK,, Zhang L . 2005. A specific role of integrin Mac-1 in accelerated macrophage efflux to the lymphatics. Blood 106 : 3234 3241.
59. Gautier EL,, Ivanov S,, Lesnik P,, Randolph GJ . 2013. Local apoptosis mediates clearance of macrophages from resolving inflammation in mice. Blood 122 : 2714 2722.
60. Gibbings SL,, Goyal R,, Desch AN,, Leach SM,, Prabagar M,, Atif SM,, Bratton DL,, Janssen W,, Jakubzick CV . 2015. Transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages. Blood 126 : 1357 1366.
61. Marguet D,, Luciani MF,, Moynault A,, Williamson P,, Chimini G . 1999. Engulfment of apoptotic cells involves the redistribution of membrane phosphatidylserine on phagocyte and prey. Nat Cell Biol 1 : 454 456.
62. Petrusca DN,, Gu Y,, Adamowicz JJ,, Rush NI,, Hubbard WC,, Smith PA,, Berdyshev EV,, Birukov KG,, Lee CH,, Tuder RM,, Twigg HL III,, Vandivier RW,, Petrache I . 2010. Sphingolipid-mediated inhibition of apoptotic cell clearance by alveolar macrophages. J Biol Chem 285 : 40322 40332.
63. Henson PM,, Vandivier RW,, Douglas IS . 2006. Cell death, remodeling, and repair in chronic obstructive pulmonary disease? Proc Am Thorac Soc 3 : 713 717.
64. Hamon R,, Homan CC,, Tran HB,, Mukaro VR,, Lester SE,, Roscioli E,, Bosco MD,, Murgia CM,, Ackland ML,, Jersmann HP,, Lang C,, Zalewski PD,, Hodge SJ . 2014. Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD. PLoS One 9 : e110056. doi:10.1371/journal.pone.0110056.
65. Fernandez-Boyanapalli R,, Frasch SC,, Riches DW,, Vandivier RW,, Henson PM,, Bratton DL . 2010. PPARγ activation normalizes resolution of acute sterile inflammation in murine chronic granulomatous disease. Blood 116 : 4512 4522.
66. Nakaya M,, Tajima M,, Kosako H,, Nakaya T,, Hashimoto A,, Watari K,, Nishihara H,, Ohba M,, Komiya S,, Tani N,, Nishida M,, Taniguchi H,, Sato Y,, Matsumoto M,, Tsuda M,, Kuroda M,, Inoue K,, Kurose H . 2013. GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance. Nat Commun 4 : 1532. doi:10.1038/ncomms2540.
67. Muñoz LE,, Janko C,, Schulze C,, Schorn C,, Sarter K,, Schett G,, Herrmann M . 2010. Autoimmunity and chronic inflammation—two clearance-related steps in the etiopathogenesis of SLE. Autoimmun Rev 10 : 38 42.
68. Rupec RA,, Petropoulou T,, Belohradsky BH,, Walchner M,, Liese JG,, Plewing G,, Messer G . 2000. Lupus erythematosus tumidus and chronic discoid lupus erythematosus in carriers of X-linked chronic granulomatous disease. Eur J Dermatol 10 : 184 189.
69. Sanford AN,, Suriano AR,, Herche D,, Dietzmann K,, Sullivan KE . 2006. Abnormal apoptosis in chronic granulomatous disease and autoantibody production characteristic of lupus. Rheumatology (Oxford) 45 : 178 181.
70. Brisse E,, Wouters CH,, Matthys P . 2015. Hemophagocytic lymphohistiocytosis (HLH): a heterogeneous spectrum of cytokine-driven immune disorders. Cytokine Growth Factor Rev 26 : 263 280.
71. Usmani GN,, Woda BA,, Newburger PE . 2013. Advances in understanding the pathogenesis of HLH. Br J Haematol 161 : 609 622.
72. Fernandez-Boyanapalli RF,, Falcone EL,, Zerbe CS,, Marciano BE,, Frasch SC,, Henson PM,, Holland SM,, Bratton DL . 2015. Impaired efferocytosis in human chronic granulomatous disease is reversed by pioglitazone treatment. J Allergy Clin Immunol 136 : 1399 1401.
73. Lucas CD,, Dorward DA,, Sharma S,, Rennie J,, Felton JM,, Alessandri AL,, Duffin R,, Schwarze J,, Haslett C,, Rossi AG . 2015. Wogonin induces eosinophil apoptosis and attenuates allergic airway inflammation. Am J Respir Crit Care Med 191 : 626 636.
74. Persson C . 2015. Drug-induced death of eosinophils. Promises and pitfalls. Am J Respir Crit Care Med 191 : 605 606.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error