1887

Chapter 14 : The Regulatory Function of Eosinophils

Authors: Ting Wen1, Marc E. Rothenberg2
VIEW AFFILIATIONS HIDE AFFILIATIONS
Affiliations: 1: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229; 2: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229
Content Type: Monograph
Publication Year: 2017

Category: Microbial Genetics and Molecular Biology

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

Preview this chapter:
Preview Magnify
Zoom in
Zoomout

The Regulatory Function of Eosinophils, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819194/9781555819187_Chap14-1.gif /docserver/preview/fulltext/10.1128/9781555819194/9781555819187_Chap14-2.gif

Abstract:

Eosinophils represent a minor component of circulating leukocytes and are generally considered to be terminally differentiated as postmitotic cells, yet it is now appreciated that they can be long-lived, multifaceted granulocytes involved in a variety of regulatory functions. Like other granulocytes, eosinophils develop and differentiate in the bone marrow. Under homeostasis, eosinophils are distributed in the blood, lung, thymus, uterus, adipose tissues, mammary gland, spleen and the lamina propria of the gastrointestinal (GI) tract ( ), indicating a physiological function in each organ. Although eosinophils outside of the bone marrow are deemed as mature, recent evidence suggests the existence of multiple tissue-specific subtypes on the basis of distinct cell surface marker expression and functions ( ). Driven by eosinophil-specific chemokines (primarily eotaxins) produced at baseline and markedly upregulated after a variety of stimuli ( ), mature eosinophils are recruited from the circulation into their physiological locations and inflammatory sites, respectively. The cytokine interleukin-5 (IL-5), produced primarily by type 2 T helper (Th2) cells ( ) and type 2 innate helper lymphoid cells (ILC2) ( ), is crucial for eosinophil differentiation, priming, and survival ( ). Conversely, eosinophils also serve as a source of a variety of cytokines and growth factors closely associated with multiple immunomodulatory functions to be discussed later. Through their vast cytokine arsenal and engagement of cell contact, eosinophils modulate immune responses through an array of interactive and orchestrated mechanisms, in and fashions, by cellular and humoral mediators, in both innate and adaptive immune responses. Recently, a burgeoning body of evidence has uncovered several underappreciated roles for eosinophils that could modulate both the adaptive and innate arms of immunity. An essential goal of this chapter is to summarize the role of eosinophils in physiological and inflammatory processes in human and small mammal models in order to identify novel pharmacological targets for specific disease management.

Citation: Wen T, Rothenberg M. 2017. The Regulatory Function of Eosinophils, p 257-269. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0020-2015
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

The Regulatory Function of Eosinophils
[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555819194.chap14-1,webId=/content/author/10.1128/9781555819194.chap14-1,properties={foaf_givenname=Ting, foaf_name=Ting Wen, foaf_surname=Wen, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555819194.chap14-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555819194.chap14-2,webId=/content/author/10.1128/9781555819194.chap14-2,properties={foaf_givenname=Marc E., foaf_name=Marc E. Rothenberg, foaf_surname=Rothenberg, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555819194.chap14-aff2]]}]]
Citation: Wen T, Rothenberg M. 2017. The Regulatory Function of Eosinophils, p 257-269. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0020-2015
/content/10.1128/9781555819194.chap14.fig14-1
Figure 1

Schematic summary of eosinophil-tropic signaling and eosinophil cellular and humoral regulatory functions. EOS, eosinophils; Mast, mast cells; Epi, epithelium; ADCC, antibody-dependent cell-mediated cytotoxicity; Ag, antigen; PMN, polymorphonuclear leukocyte (neutrophil).

10.1128/9781555819194/fig14-1_thmb.gif
10.1128/9781555819194/fig14-1.gif
Image of Figure 1
Figure 1

Schematic summary of eosinophil-tropic signaling and eosinophil cellular and humoral regulatory functions. EOS, eosinophils; Mast, mast cells; Epi, epithelium; ADCC, antibody-dependent cell-mediated cytotoxicity; Ag, antigen; PMN, polymorphonuclear leukocyte (neutrophil).

Citation: Wen T, Rothenberg M. 2017. The Regulatory Function of Eosinophils, p 257-269. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0020-2015
Permissions and Reprints Request Permissions
Download as Powerpoint
/content/10.1128/9781555819194.chap14.fig14-2
Figure 2

Research tool summary and questions to be answered. Although recent advances provide tremendous insight into the regulatory functions of eosinophils, important questions remain. With the increasing number of tools available (upper panel), progress in the listed areas (lower panel, blue boxes), in the context of key eosinophil regulation elements (ovals), will be interesting and crucial to understanding the still enigmatic function of eosinophils. EOS, eosinophils; EPO-DT, EPO-driven diphtheria toxin expression mice; EMT, epithelial-mesenchymal transition; miR, microRNA; GOI, gene of interest; Tg, transgenic; (D) KO, (double) knockout; APCs, antigen-presenting cells. Gene EPX encodes the protein product of eosinophil peroxidase (EPO).

10.1128/9781555819194/fig14-2_thmb.gif
10.1128/9781555819194/fig14-2.gif
Image of Figure 2
Figure 2

Research tool summary and questions to be answered. Although recent advances provide tremendous insight into the regulatory functions of eosinophils, important questions remain. With the increasing number of tools available (upper panel), progress in the listed areas (lower panel, blue boxes), in the context of key eosinophil regulation elements (ovals), will be interesting and crucial to understanding the still enigmatic function of eosinophils. EOS, eosinophils; EPO-DT, EPO-driven diphtheria toxin expression mice; EMT, epithelial-mesenchymal transition; miR, microRNA; GOI, gene of interest; Tg, transgenic; (D) KO, (double) knockout; APCs, antigen-presenting cells. Gene EPX encodes the protein product of eosinophil peroxidase (EPO).

Citation: Wen T, Rothenberg M. 2017. The Regulatory Function of Eosinophils, p 257-269. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0020-2015
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555819194.chap14
1. Rothenberg ME,, Hogan SP . 2006. The eosinophil. Annu Rev Immunol 24 : 147– 174.[PubMed] [CrossRef]
2. Wen T,, Mingler MK,, Blanchard C,, Wahl B,, Pabst O,, Rothenberg ME . 2012. The pan-B cell marker CD22 is expressed on gastrointestinal eosinophils and negatively regulates tissue eosinophilia. J Immunol 188 : 1075– 1082.[PubMed] [CrossRef]
3. Verjan Garcia N,, Umemoto E,, Saito Y,, Yamasaki M,, Hata E,, Matozaki T,, Murakami M,, Jung YJ,, Woo SY,, Seoh JY,, Jang MH,, Aozasa K,, Miyasaka M . 2011. SIRPα/CD172a regulates eosinophil homeostasis. J Immunol 187 : 2268– 2277.[PubMed] [CrossRef]
4. Rose CE Jr,, Lannigan JA,, Kim P,, Lee JJ,, Fu SM,, Sung SS . 2010. Murine lung eosinophil activation and chemokine production in allergic airway inflammation. Cell Mol Immunol 7 : 361– 374.[PubMed] [CrossRef]
5. Conroy DM,, Williams TJ . 2001. Eotaxin and the attraction of eosinophils to the asthmatic lung. Respir Res 2 : 150– 156.[CrossRef]
6. Upadhyaya B,, Yin Y,, Hill BJ,, Douek DC,, Prussin C . 2011. Hierarchical IL-5 expression defines a subpopulation of highly differentiated human Th2 cells. J Immunol 187 : 3111– 3120.[PubMed] [CrossRef]
7. Nussbaum JC,, Van Dyken SJ,, von Moltke J,, Cheng LE,, Mohapatra A,, Molofsky AB,, Thornton EE,, Krummel MF,, Chawla A,, Liang HE,, Locksley RM . 2013. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502 : 245– 248.[PubMed] [CrossRef]
8. Hogan SP . 2009. Functional role of eosinophils in gastrointestinal inflammation. Immunol Allergy Clin North Am 29 : 129– 140, xi.[PubMed] [CrossRef]
9. Munitz A,, Brandt EB,, Mingler M,, Finkelman FD,, Rothenberg ME . 2008. Distinct roles for IL-13 and IL-4 via IL-13 receptor α1 and the type II IL-4 receptor in asthma pathogenesis. Proc Natl Acad Sci U S A 105 : 7240– 7245.[PubMed] [CrossRef]
10. Jacobsen EA,, Ochkur SI,, Pero RS,, Taranova AG,, Protheroe CA,, Colbert DC,, Lee NA,, Lee JJ . 2008. Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells. J Exp Med 205 : 699– 710.[PubMed] [CrossRef]
11. Shen HH,, Ochkur SI,, McGarry MP,, Crosby JR,, Hines EM,, Borchers MT,, Wang H,, Biechelle TL,, O’Neill KR,, Ansay TL,, Colbert DC,, Cormier SA,, Justice JP,, Lee NA,, Lee JJ . 2003. A causative relationship exists between eosinophils and the development of allergic pulmonary pathologies in the mouse. J Immunol 170 : 3296– 3305.[PubMed] [CrossRef]
12. Chu VT,, Beller A,, Rausch S,, Strandmark J,, Zanker M,, Arbach O,, Kruglov A,, Berek C . 2014. Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis. Immunity 40 : 582– 593.[PubMed] [CrossRef]
13. Jung Y,, Wen T,, Mingler MK,, Caldwell JM,, Wang YH,, Chaplin DD,, Lee EH,, Jang MH,, Woo SY,, Seoh JY,, Miyasaka M,, Rothenberg ME . 2015. IL-1β in eosinophil-mediated small intestinal homeostasis and IgA production. Mucosal Immunol 8 : 930– 942.[PubMed] [CrossRef]
14. Chu VT,, Fröhlich A,, Steinhauser G,, Scheel T,, Roch T,, Fillatreau S,, Lee JJ,, Löhning M,, Berek C . 2011. Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat Immunol 12 : 151– 159.[PubMed] [CrossRef]
15. Wong TW,, Doyle AD,, Lee JJ,, Jelinek DF . 2014. Eosinophils regulate peripheral B cell numbers in both mice and humans. J Immunol 192 : 3548– 3558.[PubMed] [CrossRef]
16. Del Pozo V,, De Andrés B,, Martín E,, Cárdaba B,, Fernández JC,, Gallardo S,, Tramón P,, Leyva-Cobian F,, Palomino P,, Lahoz C . 1992. Eosinophil as antigen-presenting cell: activation of T cell clones and T cell hybridoma by eosinophils after antigen processing. Eur J Immunol 22 : 1919– 1925.[PubMed] [CrossRef]
17. Shi HZ,, Humbles A,, Gerard C,, Jin Z,, Weller PF . 2000. Lymph node trafficking and antigen presentation by endobronchial eosinophils. J Clin Invest 105 : 945– 953.[PubMed] [CrossRef]
18. Akuthota P,, Melo RC,, Spencer LA,, Weller PF . 2012. MHC Class II and CD9 in human eosinophils localize to detergent-resistant membrane microdomains. Am J Respir Cell Mol Biol 46 : 188– 195.[PubMed] [CrossRef]
19. Wang HB,, Ghiran I,, Matthaei K,, Weller PF . 2007. Airway eosinophils: allergic inflammation recruited professional antigen-presenting cells. J Immunol 179 : 7585– 7592.[PubMed] [CrossRef]
20. Jacobsen EA,, Zellner KR,, Colbert D,, Lee NA,, Lee JJ . 2011. Eosinophils regulate dendritic cells and Th2 pulmonary immune responses following allergen provocation. J Immunol 187 : 6059– 6068.[PubMed] [CrossRef]
21. Padigel UM,, Hess JA,, Lee JJ,, Lok JB,, Nolan TJ,, Schad GA,, Abraham D . 2007. Eosinophils act as antigen-presenting cells to induce immunity to Strongyloides stercoralis in mice. J Infect Dis 196 : 1844– 1851.[PubMed] [CrossRef]
22. Garro AP,, Chiapello LS,, Baronetti JL,, Masih DT . 2011. Eosinophils elicit proliferation of naive and fungal-specific cells in vivo so enhancing a T helper type 1 cytokine profile in favour of a protective immune response against Cryptococcus neoformans infection. Immunology 134 : 198– 213.[PubMed] [CrossRef]
23. Doyle AD,, Jacobsen EA,, Ochkur SI,, McGarry MP,, Shim KG,, Nguyen DT,, Protheroe C,, Colbert D,, Kloeber J,, Neely J,, Shim KP,, Dyer KD,, Rosenberg HF,, Lee JJ,, Lee NA . 2013. Expression of the secondary granule proteins major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX) is required for eosinophilopoiesis in mice. Blood 122 : 781– 790.[PubMed] [CrossRef]
24. Spencer LA,, Szela CT,, Perez SA,, Kirchhoffer CL,, Neves JS,, Radke AL,, Weller PF . 2009. Human eosinophils constitutively express multiple Th1, Th2, and immunoregulatory cytokines that are secreted rapidly and differentially. J Leukoc Biol 85 : 117– 123.[PubMed] [CrossRef]
25. Odemuyiwa SO,, Ghahary A,, Li Y,, Puttagunta L,, Lee JE,, Musat-Marcu S,, Ghahary A,, Moqbel R . 2004. Cutting edge: human eosinophils regulate T cell subset selection through indoleamine 2,3-dioxygenase. J Immunol 173 : 5909– 5913.[PubMed] [CrossRef]
26. Lotfi R,, Lotze MT . 2008. Eosinophils induce DC maturation, regulating immunity. J Leukoc Biol 83 : 456– 460.[PubMed] [CrossRef]
27. Weir MR,, Hall-Craggs M,, Shen SY,, Posner JN,, Alongi SV,, Dagher FJ,, Sadler JH . 1986. The prognostic value of the eosinophil in acute renal allograft rejection. Transplantation 41 : 709– 712.[PubMed] [CrossRef]
28. Lotfi R,, Lee JJ,, Lotze MT . 2007. Eosinophilic granulocytes and damage-associated molecular pattern molecules (DAMPs): role in the inflammatory response within tumors. J Immunother 30 : 16– 28.[PubMed] [CrossRef]
29. Yang D,, Rosenberg HF,, Chen Q,, Dyer KD,, Kurosaka K,, Oppenheim JJ . 2003. Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells. Blood 102 : 3396– 3403.[PubMed] [CrossRef]
30. Yang D,, Chen Q,, Rosenberg HF,, Rybak SM,, Newton DL,, Wang ZY,, Fu Q,, Tchernev VT,, Wang M,, Schweitzer B,, Kingsmore SF,, Patel DD,, Oppenheim JJ,, Howard OM . 2004. Human ribonuclease A superfamily members, eosinophil-derived neurotoxin and pancreatic ribonuclease, induce dendritic cell maturation and activation. J Immunol 173 : 6134– 6142.[PubMed] [CrossRef]
31. Yang D,, Chen Q,, Su SB,, Zhang P,, Kurosaka K,, Caspi RR,, Michalek SM,, Rosenberg HF,, Zhang N,, Oppenheim JJ . 2008. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. J Exp Med 205 : 79– 90.[PubMed] [CrossRef]
32. O’Connell AE,, Hess JA,, Santiago GA,, Nolan TJ,, Lok JB,, Lee JJ,, Abraham D . 2011. Major basic protein from eosinophils and myeloperoxidase from neutrophils are required for protective immunity to Strongyloides stercoralis in mice. Infect Immun 79 : 2770– 2778.[PubMed] [CrossRef]
33. Tulic MK,, Sly PD,, Andrews D,, Crook M,, Davoine F,, Odemuyiwa SO,, Charles A,, Hodder ML,, Prescott SL,, Holt PG,, Moqbel R . 2009. Thymic indoleamine 2,3-dioxygenase-positive eosinophils in young children: potential role in maturation of the naive immune system. Am J Pathol 175 : 2043– 2052.[PubMed] [CrossRef]
34. Throsby M,, Herbelin A,, Pléau JM,, Dardenne M . 2000. CD11c + eosinophils in the murine thymus: developmental regulation and recruitment upon MHC class I-restricted thymocyte deletion. J Immunol 165 : 1965– 1975.[PubMed] [CrossRef]
35. Yousefi S,, Gold JA,, Andina N,, Lee JJ,, Kelly AM,, Kozlowski E,, Schmid I,, Straumann A,, Reichenbach J,, Gleich GJ,, Simon HU . 2008. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat Med 14 : 949– 953.[PubMed] [CrossRef]
36. Ueki S,, Melo RC,, Ghiran I,, Spencer LA,, Dvorak AM,, Weller PF . 2013. Eosinophil extracellular DNA trap cell death mediates lytic release of free secretion-competent eosinophil granules in humans. Blood 121 : 2074– 2083.[PubMed] [CrossRef]
37. Klion AD,, Nutman TB . 2004. The role of eosinophils in host defense against helminth parasites. J Allergy Clin Immunol 113 : 30– 37.[PubMed] [CrossRef]
38. Kephart GM,, Gleich GJ,, Connor DH,, Gibson DW,, Ackerman SJ . 1984. Deposition of eosinophil granule major basic protein onto microfilariae of Onchocerca volvulus in the skin of patients treated with diethylcarbamazine. Lab Invest 50 : 51– 61.[PubMed]
39. Mehlotra RK,, Hall LR,, Higgins AW,, Dreshaj IA,, Haxhiu MA,, Kazura JW,, Pearlman E . 1998. Interleukin-12 suppresses filaria-induced pulmonary eosinophilia, deposition of major basic protein and airway hyperresponsiveness. Parasite Immunol 20 : 455– 462.[PubMed] [CrossRef]
40. Specht S,, Saeftel M,, Arndt M,, Endl E,, Dubben B,, Lee NA,, Lee JJ,, Hoerauf A . 2006. Lack of eosinophil peroxidase or major basic protein impairs defense against murine filarial infection. Infect Immun 74 : 5236– 5243.[PubMed] [CrossRef]
41. Bandeira-Melo C,, Weller PF . 2005. Mechanisms of eosinophil cytokine release. Mem Inst Oswaldo Cruz 100( Suppl 1) : 73– 81.[PubMed] [CrossRef]
42. Elsner J,, Oppermann M,, Kapp A . 1996. Detection of C5a receptors on human eosinophils and inhibition of eosinophil effector functions by anti-C5a receptor (CD88) antibodies. Eur J Immunol 26 : 1560– 1564.[PubMed] [CrossRef]
43. Nagase H,, Okugawa S,, Ota Y,, Yamaguchi M,, Tomizawa H,, Matsushima K,, Ohta K,, Yamamoto K,, Hirai K . 2003. Expression and function of Toll-like receptors in eosinophils: activation by Toll-like receptor 7 ligand. J Immunol 171 : 3977– 3982.[PubMed] [CrossRef]
44. Mansson A,, Cardell LO . 2009. Role of atopic status in Toll-like receptor (TLR)7- and TLR9-mediated activation of human eosinophils. J Leukoc Biol 85 : 719– 727.[PubMed] [CrossRef]
45. Wong CK,, Cheung PF,, Ip WK,, Lam CW . 2007. Intracellular signaling mechanisms regulating Toll-like receptor-mediated activation of eosinophils. Am J Respir Cell Mol Biol 37 : 85– 96.[PubMed] [CrossRef]
46. Guilbert TW,, Denlinger LC . 2010. Role of infection in the development and exacerbation of asthma. Expert Rev Respir Med 4 : 71– 83.[PubMed] [CrossRef]
47. Driss V,, Legrand F,, Hermann E,, Loiseau S,, Guerardel Y,, Kremer L,, Adam E,, Woerly G,, Dombrowicz D,, Capron M . 2009. TLR2-dependent eosinophil interactions with mycobacteria: role of α-defensins. Blood 113 : 3235– 3244.[PubMed] [CrossRef]
48. Bedoya VI,, Boasso A,, Hardy AW,, Rybak S,, Shearer GM,, Rugeles MT . 2006. Ribonucleases in HIV type 1 inhibition: effect of recombinant RNases on infection of primary T cells and immune activation-induced RNase gene and protein expression. AIDS Res Hum Retroviruses 22 : 897– 907.[PubMed] [CrossRef]
49. Phipps S,, Lam CE,, Mahalingam S,, Newhouse M,, Ramirez R,, Rosenberg HF,, Foster PS,, Matthaei KI . 2007. Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus. Blood 110 : 1578– 1586.[PubMed] [CrossRef]
50. Soukup JM,, Becker S . 2003. Role of monocytes and eosinophils in human respiratory syncytial virus infection in vitro. Clin Immunol 107 : 178– 185.[CrossRef]
51. Mathur SK,, Fichtinger PS,, Kelly JT,, Lee WM,, Gern JE,, Jarjour NN . 2013. Interaction between allergy and innate immunity: model for eosinophil regulation of epithelial cell interferon expression. Ann Allergy Asthma Immunol 111 : 25– 31.[PubMed] [CrossRef]
52. Knipping K,, McNeal MM,, Crienen A,, van Amerongen G,, Garssen J,, Van’t Land B . 2011. A gastrointestinal rotavirus infection mouse model for immune modulation studies. Virol J 8 : 109. doi:10.1186/1743-422X-8-109.
53. Gudbjartsson DF,, Bjornsdottir US,, Halapi E,, Helgadottir A,, Sulem P,, Jonsdottir GM,, Thorleifsson G,, Helgadottir H,, Steinthorsdottir V,, Stefansson H,, Williams C,, Hui J,, Beilby J,, Warrington NM,, James A,, Palmer LJ,, Koppelman GH,, Heinzmann A,, Krueger M,, Boezen HM,, Wheatley A,, Altmuller J,, Shin HD,, Uh ST,, Cheong HS,, Jonsdottir B,, Gislason D,, Park CS,, Rasmussen LM,, Porsbjerg C,, Hansen JW,, Backer V,, Werge T,, Janson C,, Jönsson UB,, Ng MC,, Chan J,, So WY,, Ma R,, Shah SH,, Granger CB,, Quyyumi AA,, Levey AI,, Vaccarino V,, Reilly MP,, Rader DJ,, Williams MJ,, van Rij AM,, Jones GT,, Trabetti E,, Malerba G,, Pignatti PF,, Boner A,, Pescollderungg L,, Girelli D,, Olivieri O,, Martinelli N,, Ludviksson BR,, Ludviksdottir D,, Eyjolfsson GI,, Arnar D,, Thorgeirsson G,, Deichmann K,, Thompson PJ,, Wjst M,, Hall IP,, Postma DS,, Gislason T,, Gulcher J,, Kong A,, Jonsdottir I,, Thorsteinsdottir U,, Stefansson K . 2009. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 41 : 342– 347.[PubMed] [CrossRef]
54. Lefkowitz DL,, Lincoln JA,, Howard KR,, Stuart R,, Lefkowitz SS,, Allen RC . 1997. Macrophage-mediated candidacidal activity is augmented by exposure to eosinophil peroxidase: a paradigm for eosinophil-macrophage interaction. Inflammation 21 : 159– 172.[PubMed] [CrossRef]
55. Furuta GT,, Nieuwenhuis EE,, Karhausen J,, Gleich G,, Blumberg RS,, Lee JJ,, Ackerman SJ . 2005. Eosinophils alter colonic epithelial barrier function: role for major basic protein. Am J Physiol Gastrointest Liver Physiol 289 : G890– G897.[PubMed] [CrossRef]
56. Hirata A,, Motojima S,, Fukuda T,, Makino S . 1996. Damage to respiratory epithelium by guinea-pig eosinophils stimulated with IgG-coated Sepharose beads. Clin Exp Allergy 26 : 848– 858.[PubMed] [CrossRef]
57. Ricciardolo FL,, Di Stefano A,, van Krieken JH,, Sont JK,, van Schadewijk A,, Rabe KF,, Donner CF,, Hiemstra PS,, Sterk PJ,, Mauad T . 2003. Proliferation and inflammation in bronchial epithelium after allergen in atopic asthmatics. Clin Exp Allergy 33 : 905– 911.[PubMed] [CrossRef]
58. Burgel PR,, Lazarus SC,, Tam DC,, Ueki IF,, Atabai K,, Birch M,, Nadel JA . 2001. Human eosinophils induce mucin production in airway epithelial cells via epidermal growth factor receptor activation. J Immunol 167 : 5948– 5954.[PubMed] [CrossRef]
59. Bradding P . 2008. Asthma: eosinophil disease, mast cell disease, or both? Allergy Asthma Clin Immunol 4 : 84– 90.[PubMed] [CrossRef]
60. Radke AL,, Reynolds LE,, Melo RC,, Dvorak AM,, Weller PF,, Spencer LA . 2009. Mature human eosinophils express functional Notch ligands mediating eosinophil autocrine regulation. Blood 113 : 3092– 3101.[PubMed] [CrossRef]
61. Robinson DS,, Kariyawasam HH . 2015. Mepolizumab for eosinophilic severe asthma: recent studies. Expert Opin Biol Ther 15 : 909– 914.[PubMed] [CrossRef]
62. Ortega HG,, Liu MC,, Pavord ID,, Brusselle GG,, FitzGerald JM,, Chetta A,, Humbert M,, Katz LE,, Keene ON,, Yancey SW,, Chanez P , MENSA Investigators . 2014. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 371 : 1198– 1207.[PubMed] [CrossRef]
63. Pavord ID,, Korn S,, Howarth P,, Bleecker ER,, Buhl R,, Keene ON,, Ortega H,, Chanez P . 2012. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380 : 651– 659.[CrossRef]
64. Castro M,, Zangrilli J,, Wechsler ME,, Bateman ED,, Brusselle GG,, Bardin P,, Murphy K,, Maspero JF,, O’Brien C,, Korn S . 2015. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 3 : 355– 366.[CrossRef]
65. Reichert JM . 2015. Antibodies to watch in 2015. MAbs 7 : 1– 8.[PubMed] [CrossRef]
66. Rothenberg ME . 2016. Humanized anti-IL-5 antibody therapy. Cell 165 : 509. doi:10.1016/j.cell.2016.04.020. [CrossRef]
67. Persson T,, Monsef N,, Andersson P,, Bjartell A,, Malm J,, Calafat J,, Egesten A . 2003. Expression of the neutrophil-activating CXC chemokine ENA-78/CXCL5 by human eosinophils. Clin Exp Allergy 33 : 531– 537.[PubMed] [CrossRef]
68. Page SM,, Gleich GJ,, Roebuck KA,, Thomas LL . 1999. Stimulation of neutrophil interleukin-8 production by eosinophil granule major basic protein. Am J Respir Cell Mol Biol 21 : 230– 237.[PubMed] [CrossRef]
69. Simpson JL,, Grissell TV,, Douwes J,, Scott RJ,, Boyle MJ,, Gibson PG . 2007. Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax 62 : 211– 218.[PubMed] [CrossRef]
70. Singh N,, Phillips RA,, Iscove NN,, Egan SE . 2000. Expression of Notch receptors, Notch ligands, and Fringe genes in hematopoiesis. Exp Hematol 28 : 527– 534.[CrossRef]
71. Wang YC,, He F,, Feng F,, Liu XW,, Dong GY,, Qin HY,, Hu XB,, Zheng MH,, Liang L,, Feng L,, Liang YM,, Han H . 2010. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res 70 : 4840– 4849.[PubMed] [CrossRef]
72. Bailis W,, Yashiro-Ohtani Y,, Fang TC,, Hatton RD,, Weaver CT,, Artis D,, Pear WS . 2013. Notch simultaneously orchestrates multiple helper T cell programs independently of cytokine signals. Immunity 39 : 148– 159.[PubMed] [CrossRef]
73. Haldar P,, Brightling CE,, Hargadon B,, Gupta S,, Monteiro W,, Sousa A,, Marshall RP,, Bradding P,, Green RH,, Wardlaw AJ,, Pavord ID . 2009. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 360 : 973– 984.[PubMed] [CrossRef]
74. Al-Muhsen S,, Johnson JR,, Hamid Q . 2011. Remodeling in asthma. J Allergy Clin Immunol 128 : 451– 462; quiz 463–464.[PubMed] [CrossRef]
75. Venge P . 2010. The eosinophil and airway remodelling in asthma. Clin Respir J 4( Suppl 1) : 15– 19.[PubMed] [CrossRef]
76. Zagai U,, Lundahl J,, Klominek J,, Venge P,, Sköld CM . 2009. Eosinophil cationic protein stimulates migration of human lung fibroblasts in vitro . Scand J Immunol 69 : 381– 386.[PubMed] [CrossRef]
77. Zagai U,, Dadfar E,, Lundahl J,, Venge P,, Sköld CM . 2007. Eosinophil cationic protein stimulates TGF-β 1 release by human lung fibroblasts in vitro . Inflammation 30 : 153– 160.[PubMed] [CrossRef]
78. Abonia JP,, Blanchard C,, Butz BB,, Rainey HF,, Collins MH,, Stringer K,, Putnam PE,, Rothenberg ME . 2010. Involvement of mast cells in eosinophilic esophagitis. J Allergy Clin Immunol 126 : 140– 149.[PubMed] [CrossRef]
79. O’Sullivan S . 1999. On the role of PGD 2 metabolites as markers of mast cell activation in asthma. Acta Physiol Scand Suppl 644 : 1– 74.[PubMed]
80. Dahlén SE,, Kumlin M . 2004. Monitoring mast cell activation by prostaglandin D 2 in vivo. Thorax 59 : 453– 455.[PubMed] [CrossRef]
81. Kataoka N,, Satoh T,, Hirai A,, Saeki K,, Yokozeki H . 2013. Indomethacin inhibits eosinophil migration to prostaglandin D 2: therapeutic potential of CRTH2 desensitization for eosinophilic pustular folliculitis. Immunology 140 : 78– 86.[PubMed] [CrossRef]
82. Kagawa S,, Fukunaga K,, Oguma T,, Suzuki Y,, Shiomi T,, Sayama K,, Kimura T,, Hirai H,, Nagata K,, Nakamura M,, Asano K . 2011. Role of prostaglandin D 2 receptor CRTH2 in sustained eosinophil accumulation in the airways of mice with chronic asthma. Int Arch Allergy Immunol 155( Suppl 1) : 6– 11.[PubMed] [CrossRef]
83. Cosmi L,, Annunziato F,, Galli MI,, Maggi RM,, Nagata K,, Romagnani S . 2000. CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease. Eur J Immunol 30 : 2972– 2979.[CrossRef]
84. Otani IM,, Anilkumar AA,, Newbury RO,, Bhagat M,, Beppu LY,, Dohil R,, Broide DH,, Aceves SS . 2013. Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis. J Allergy Clin Immunol 131 : 1576– 1582.[PubMed] [CrossRef]
85. Osterfeld H,, Ahrens R,, Strait R,, Finkelman FD,, Renauld JC,, Hogan SP . 2010. Differential roles for the IL-9/IL-9 receptor α-chain pathway in systemic and oral antigen-induced anaphylaxis. J Allergy Clin Immunol 125 : 469– 476.e462. doi:10.1016/j.jaci.2009.09.054. [CrossRef]
86. Minai-Fleminger Y,, Elishmereni M,, Vita F,, Soranzo MR,, Mankuta D,, Zabucchi G,, Levi-Schaffer F . 2010. Ultrastructural evidence for human mast cell-eosinophil interactions in vitro. Cell Tissue Res 341 : 405– 415.[PubMed] [CrossRef]
87. Numata Y,, Terui T,, Okuyama R,, Hirasawa N,, Sugiura Y,, Miyoshi I,, Watanabe T,, Kuramasu A,, Tagami H,, Ohtsu H . 2006. The accelerating effect of histamine on the cutaneous wound-healing process through the action of basic fibroblast growth factor. J Invest Dermatol 126 : 1403– 1409.[PubMed] [CrossRef]
88. Reher TM,, Neumann D,, Buschauer A,, Seifert R . 2012. Incomplete activation of human eosinophils via the histamine H 4-receptor: evidence for ligand-specific receptor conformations. Biochem Pharmacol 84 : 192– 203.[PubMed] [CrossRef]
89. Stenfeldt AL,, Wenneras C . 2004. Danger signals derived from stressed and necrotic epithelial cells activate human eosinophils. Immunology 112 : 605– 614.[PubMed] [CrossRef]
90. Todd R,, Donoff BR,, Chiang T,, Chou MY,, Elovic A,, Gallagher GT,, Wong DT . 1991. The eosinophil as a cellular source of transforming growth factor alpha in healing cutaneous wounds. Am J Pathol 138 : 1307– 1313.[PubMed]
91. Ohno I,, Nitta Y,, Yamauchi K,, Hoshi H,, Honma M,, Woolley K,, O’Byrne P,, Dolovich J,, Jordana M,, Tamura G . 1995. Eosinophils as a potential source of platelet-derived growth factor B-chain (PDGF-B) in nasal polyposis and bronchial asthma. Am J Respir Cell Mol Biol 13 : 639– 647.[PubMed] [CrossRef]
92. Horiuchi T,, Weller PF . 1997. Expression of vascular endothelial growth factor by human eosinophils: upregulation by granulocyte macrophage colony-stimulating factor and interleukin-5. Am J Respir Cell Mol Biol 17 : 70– 77.[PubMed] [CrossRef]
93. Goh YP,, Henderson NC,, Heredia JE,, Red Eagle A,, Odegaard JI,, Lehwald N,, Nguyen KD,, Sheppard D,, Mukundan L,, Locksley RM,, Chawla A . 2013. Eosinophils secrete IL-4 to facilitate liver regeneration. Proc Natl Acad Sci U S A 110 : 9914– 9919.[PubMed] [CrossRef]
94. Elovic AE,, Gallagher GT,, Kabani S,, Galli SJ,, Weller PF,, Wong DT . 1996. Lack of TGF-alpha and TGF-beta 1 synthesis by human eosinophils in chronic oral ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81 : 672– 681.[CrossRef]
95. Yang J,, Torio A,, Donoff RB,, Gallagher GT,, Egan R,, Weller PF,, Wong DT . 1997. Depletion of eosinophil infiltration by anti-IL-5 monoclonal antibody (TRFK-5) accelerates open skin wound epithelial closure. Am J Pathol 151 : 813– 819.[PubMed]
96. Leitch VD,, Strudwick XL,, Matthaei KI,, Dent LA,, Cowin AJ . 2009. IL-5-overexpressing mice exhibit eosinophilia and altered wound healing through mechanisms involving prolonged inflammation. Immunol Cell Biol 87 : 131– 140.[PubMed] [CrossRef]
97. Mills CD . 2012. M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol 32 : 463– 488.[PubMed] [CrossRef]
98. Sica A,, Mantovani A . 2012. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122 : 787– 795.[PubMed] [CrossRef]
99. Fujisaka S,, Usui I,, Bukhari A,, Ikutani M,, Oya T,, Kanatani Y,, Tsuneyama K,, Nagai Y,, Takatsu K,, Urakaze M,, Kobayashi M,, Tobe K . 2009. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58 : 2574– 2582.[PubMed] [CrossRef]
100. Wu D,, Molofsky AB,, Liang HE,, Ricardo-Gonzalez RR,, Jouihan HA,, Bando JK,, Chawla A,, Locksley RM . 2011. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332 : 243– 247.[PubMed] [CrossRef]
101. Foster EL,, Simpson EL,, Fredrikson LJ,, Lee JJ,, Lee NA,, Fryer AD,, Jacoby DB . 2011. Eosinophils increase neuron branching in human and murine skin and in vitro . PLoS One 6 : e22029. doi:10.1371/journal.pone.0022029.
102. Fryer AD,, Stein LH,, Nie Z,, Curtis DE,, Evans CM,, Hodgson ST,, Jose PJ,, Belmonte KE,, Fitch E,, Jacoby DB . 2006. Neuronal eotaxin and the effects of CCR3 antagonist on airway hyperreactivity and M2 receptor dysfunction. J Clin Invest 116 : 228– 236.[PubMed] [CrossRef]
103. Kobayashi H,, Gleich GJ,, Butterfield JH,, Kita H . 2002. Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli. Blood 99 : 2214– 2220.[PubMed] [CrossRef]
104. Wen T,, Stucke EM,, Grotjan TM,, Kemme KA,, Abonia JP,, Putnam PE,, Franciosi JP,, Garza JM,, Kaul A,, King EC,, Collins MH,, Kushner JP,, Rothenberg ME . 2013. Molecular diagnosis of eosinophilic esophagitis by gene expression profiling. Gastroenterology 145 : 1289– 1299.[PubMed] [CrossRef]
105. Noel RJ,, Putnam PE,, Rothenberg ME . 2004. Eosinophilic esophagitis. N Engl J Med 351 : 940– 941.[PubMed] [CrossRef]
106. Hahn C,, Islamian AP,, Renz H,, Nockher WA . 2006. Airway epithelial cells produce neurotrophins and promote the survival of eosinophils during allergic airway inflammation. J Allergy Clin Immunol 117 : 787– 794.[PubMed] [CrossRef]
107. Sanico AM,, Koliatsos VE,, Stanisz AM,, Bienenstock J,, Togias A . 1999. Neural hyperresponsiveness and nerve growth factor in allergic rhinitis. Int Arch Allergy Immunol 118 : 154– 158.[PubMed] [CrossRef]
108. Peters EM,, Liezmann C,, Spatz K,, Daniltchenko M,, Joachim R,, Gimenez-Rivera A,, Hendrix S,, Botchkarev VA,, Brandner JM,, Klapp BF . 2011. Nerve growth factor partially recovers inflamed skin from stress-induced worsening in allergic inflammation. J Invest Dermatol 131 : 735– 743.[PubMed] [CrossRef]
109. Furuta GT,, Forbes D,, Boey C,, Dupont C,, Putnam P,, Roy S,, Sabra A,, Salvatierra A,, Yamashiro Y,, Husby S , Eosinophilic Gastrointestinal Diseases Working Group . 2008. Eosinophilic gastrointestinal diseases (EGIDs). J Pediatr Gastroenterol Nutr 47 : 234– 238.[PubMed] [CrossRef]
110. Blanchard C,, Rothenberg ME . 2008. Basic pathogenesis of eosinophilic esophagitis. Gastrointest Endosc Clin N Am 18 : 133– 143; x.[PubMed] [CrossRef]
111. Jacoby DB,, Costello RM,, Fryer AD . 2001. Eosinophil recruitment to the airway nerves. J Allergy Clin Immunol 107 : 211– 218.[PubMed] [CrossRef]
112. Yost BL,, Gleich GJ,, Fryer AD . 1999. Ozone-induced hyperresponsiveness and blockade of M2 muscarinic receptors by eosinophil major basic protein. J Appl Physiol 87 : 1272– 1278.[PubMed]
113. Kita H . 2011. Eosinophils: multifaceted biological properties and roles in health and disease. Immunol Rev 242 : 161– 177.[PubMed] [CrossRef]
114. Carlens J,, Wahl B,, Ballmaier M,, Bulfone-Paus S,, Forster R,, Pabst O . 2009. Common γ-chain-dependent signals confer selective survival of eosinophils in the murine small intestine. J Immunol 183 : 5600– 5607.[PubMed] [CrossRef]
115. Matsuoka K,, Shitara H,, Taya C,, Kohno K,, Kikkawa Y,, Yonekawa H . 2013. Novel basophil- or eosinophil-depleted mouse models for functional analyses of allergic inflammation. PLoS One 8 : e60958. doi:10.1371/journal.pone.0060958. [CrossRef]
116. Moro K,, Yamada T,, Tanabe M,, Takeuchi T,, Ikawa T,, Kawamoto H,, Furusawa J,, Ohtani M,, Fujii H,, Koyasu S . 2010. Innate production of T H2 cytokines by adipose tissue-associated c-Kit +Sca-1 + lymphoid cells. Nature 463 : 540– 544.[PubMed] [CrossRef]
117. Doyle AD,, Jacobsen EA,, Ochkur SI,, Willetts L,, Shim K,, Neely J,, Kloeber J,, Lesuer WE,, Pero RS,, Lacy P,, Moqbel R,, Lee NA,, Lee JJ . 2013. Homologous recombination into the eosinophil peroxidase locus generates a strain of mice expressing Cre recombinase exclusively in eosinophils. J Leukoc Biol 94 : 17– 24.[PubMed] [CrossRef]

Back to top
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