REVIEWS Eosinophils: changing perspectives in health and disease Helene F. Rosenberg1, Kimberly D. Dyer1 and Paul S. Foster2 Abstract | Eosinophils have been traditionally perceived as terminally differentiated cytotoxic effector cells. Recent studies have profoundly altered this simplistic view of eosinophils and their function. New insights into the molecular pathways that control the development, trafficking and degranulation of eosinophils have improved our understanding of the immunomodulatory functions of these cells and their roles in promoting homeostasis. Likewise, recent developments have generated a more sophisticated view of how eosinophils contribute to the pathogenesis of different diseases, including asthma and primary hypereosinophilic syndromes, and have also provided us with a more complete appreciation of the activities of these cells during parasitic infection. Eosinophils were first described in 1879 by Paul Ehrlich, to airway dysfunction and tissue remodelling in this who noted their unusual capacity to be stained by acido­ disorder8,9. Evolution tells us that the ability to induce philic dyes. Interestingly, our appreciation of this unique pathology cannot be a ‘raison d’être’ for any existing property of eosinophils is clear and steadfast, but a com­ cell lineage, and recent findings on the antimicrobial prehensive understanding of the function of these cells and antiviral activities of eosinophils suggest that the in health and disease remains elusive. Some basic char­ pathology that arises from dysregulated eosinophilia acteristics of eosinophils are established and accepted. in the airways may be collateral damage related to It is clear that eosinophils are granulocytes that develop host defence. Similarly, although there are now two in the bone marrow from pluripotent progenitors. They unique eosinophil-deficient mouse strains10,11, there are released into the peripheral blood in a phenotypi­ are no known unique eosinophil-deficiency states in cally mature state, and they are capable of being activated humans to help us to decipher the importance of these and recruited into tissues in response to appropriate cells in vivo. stimuli, most notably the cytokine interleukin‑5 (IL‑5) This Review examines the most recent advances in and the eotaxin chemokines. Eosinophils spend only our understanding of the contributions of eosinophils 1Laboratory of Allergic a brief time in the peripheral blood (they have a half- to the maintenance of health, and how dysregulated Diseases, National Institute 1 of Allergy and Infectious life of ~18 hrs) before they migrate to the thymus or eosinophil function promotes various disease states. Diseases, National Institutes gastrointestinal tract, where they reside under homeo­ These advances were made possible by reagents, systems of Health, Bethesda, static conditions2. In response to inflammatory stimuli, and methods that target eosinophil function and by the Maryland 20892, USA. eosinophils develop from committed bone marrow first clinical trials using humanized monoclonal anti­ 2 Priority Research Centre for progenitors, after which they exit the bone marrow, bodies specific for IL‑5 (TABLE 1). These tools have been Asthma and Respiratory Diseases, Kookaburra Way, migrate into the blood and subsequently accumulate invaluable for shaping our current views on eosinophil Hunter Medical Research in peripheral tissues, where their survival is prolonged function and for generating new hypotheses for future Institute and School of (reviewed in REFS 3–5). examination. Biomedical Sciences and However, much remains unclear. For example, the Pharmacy, Faculty of Health, The unique biology of the eosinophil University of Newcastle, long-held belief that eosinophils promote immunity Newcastle, NSW 2300, to helminths has been called into question by results Relatively few mature eosinophils are found in the Australia. from animal studies, some of which suggest that peripheral blood of healthy humans (less than 400 Correspondence to H.F.R. eosinophils may be serving to promote the needs and per mm3), but these cells can be readily distinguished e-mail: longevity of specific parasites6,7. Likewise, eosinophils from the more prevalent neutrophils by virtue of their [email protected] (FIG. 1) doi:10.1038/nri3341 are clearly recruited to and activated in lung tissue bilobed nuclei and large specific granules . Human Published online as part of the pathophysiology of asthma, and most eosinophil granules contain four major proteins: eosino­ 16 November 2012 current evidence suggests that eosinophils contribute phil peroxidase, major basic protein (MBP) and the NATURE REVIEWS | IMMUNOLOGY VOLUME 13 | JANUARY 2013 | 9 © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Table 1 | Tools for the eosinophil biologist System Specific reagent or model Characteristics Refs Cytological stains Modified Giemsa Stains the nucleus blue and granules bright red 148 Sirius red Stains the nucleus blue and granules red 149 Fast green and neutral red Stains the nucleus red and granules bright green 150 Laboratory antibodies Antibody specific for mouse IL‑5Rα Binds to the receptor for IL‑5 151 for the detection of eosinophils by flow Antibody specific for mouse Binds to a sialic acid-binding immunoglobulin-like lectin expressed by 148 cytometry SIGLEC-F eosinophils Antibody specific for mouse CCR3 Binds to the receptor for the eotaxins 152 Laboratory antibodies Antibody specific for human EPX Monoclonal; does not cross-react with myeloperoxidase 153 for the detection of eosinophils by Antibody specific for mouse major Binds to an eosinophil granule protein 154 immunohistochemistry basic protein ELISA assays ELISA for human EDN Targets an eosinophil granule protein 155 ELISA for mouse EPX Targets an eosinophil granule protein 156 In vivo eosinophil Treatment with TRFK5 antibody Rat monoclonal antibody that targets mouse IL‑5 157 depletion Treatment with antibodies specific Rat antibodies that target mouse CCR3 158 for mouse CCR3 Treatment with antibodies specific Depletes eosinophils by targeting a sialic acid-binding 159 for mouse SIGLEC-F immunoglobulin-like lectin Methods for generating Culture of human CD34+ bone A cytokine-based method for generating eosinophils from human CD34+ 133 eosinophils ex vivo marrow cells with IL‑5, IL‑3 and cells in vitro GM‑CSF Culture of mouse bone marrow cells A cytokine-based method for generating eosinophils from unselected 160 with SCF, FLT3L and IL‑5 mouse bone marrow progenitors in vitro Mouse strains ΔdblGATA mice Deletion of a palindromic GATA-binding site in the promoter of Gata1 10 for manipulating results in the unique loss of cells of the eosinophil lineage eosinophils TgPHIL mice The expression of diphtheria toxin A under the control of the Epx 11 promoter results in the loss of eosinophil promyelocytes in the bone marrow −/− Il5 mice Il5 gene deletion; no eosinophilia in response to TH2 cell‑inducing stimuli, 161 although baseline eosinophil counts remain normal Il5ra−/− mice Il5ra gene deletion; no eosinophilia in response to IL‑5 162 Cd2‑IL‑5‑transgenic mice IL‑5 overexpression is driven by the lymphocyte Cd2 promoter, resulting in 163 systemic eosinophilia Cd3δ‑IL‑5‑transgenic (NJ.1638) mice IL‑5 overexpression is driven by the T cell Cd3δ promoter and enhancer 164 region, resulting in systemic eosinophilia Ccl11−/− mice Ccl11 gene deletion, resulting in diminished recruitment of eosinophils to 165 the lungs and gastrointestinal tract Ccl24−/− mice Ccl24 gene deletion; CCL24 is the dominant chemokine for allergen- 166 associated eosinophil recruitment to the lungs Ccl11−/−Ccl24−/− mice Dual deletion results in profoundly diminished eosinophil recruitment in 167 response to allergen sensitization and challenge IL‑5/CCL24 double-transgenic mice Overexpression of IL‑5 (as in NJ.1638 mice) and CCL24 (under the 168 control of the lung-specific Cc10 promoter) elicits profound pulmonary eosinophilia and eosinophil degranulation in situ Ccr3−/− mice Gene deletion of the receptor for eotaxins, resulting in diminished 169 recruitment of eosinophils to tissues Siglecf−/− mice Exaggerated eosinophil responses and delayed resolution of lung 170 eosinophilia in response to allergen challenge Humanized IgG1‑isotype antibodies specific Indirectly target eosinophils by depleting IL‑5 96,137, monoclonal antibodies for human IL‑5 (mepolizumab and 171 for clinical applications reslizumab (humanized TRFK5)) IgG1‑isotype antibody specific for Mediates the antibody-dependent cytotoxic destruction of eosinophils 96 human IL‑5Rα (benralizumab) by targeting IL‑5Rα CCL, CC-chemokine ligand; CCR3, CC-chemokine receptor 3; EDN, eosinophil-derived neurotoxin; ELISA, enzyme-linked immunosorbent assay; EPX, eosinophil peroxidase; FLT3L, FMS-like tyrosine kinase 3 ligand; GATA1, GATA-binding protein 1; GM‑CSF, granulocyte–macrophage colony-stimulating factor; IL, interleukin; IL‑5Rα, IL‑5 receptor subunit-α; SCF, stem cell factor; SIGLEC-F, sialic acid-binding immunoglobulin-like lectin F; TH2, T helper 2. 10 | JANUARY 2013 | VOLUME 13 www.nature.com/reviews/immunol © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Innate lymphoid cells ribonucleases eosinophil cationic protein (ECP) and Factors that promote eosinophilia Cells that produce cytokines eosinophil-derived neurotoxin (EDN). The granules IL‑5 has a central and profound role in all aspects of typically attributed to T helper also store numerous cytokines, enzymes and growth eosinophil development,