Eosinophils unleashed

From www.bloodjournal.org at TEL AVIV UNIV on January 5, 2011. For personal use only.

2008 111: 5423doi:10.1182/blood-2008-03-146837

Eosinophils unleashed Helene F. Rosenberg

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From www.bloodjournal.org at TEL AVIV UNIV on January 5, 2011. For personal use only.

3. Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol. 2008; 180:2581-2587. 4. Brazelton TR, Rossi FM, Keshet GI, Blau HM. From

marrow to brain: expression of neuronal phenotypes in adult mice. Science. 2000;290:1775-1779. 5. Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000;290:1779-1782.

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Comment on Munitz et al, page 5694

Eosinophils unleashed ---------------------------------------------------------------------------------------------------------------Helene F. Rosenberg

NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASE (NIAID) LABORATORY

OF ALLERGIC DISEASES

In this issue of Blood, Munitz and colleagues demonstrate pronounced expression of the inhibitory receptor known as paired immunoglobulin-like receptor (PIR)–B on the surface of mouse eosinophils. IRs were first identified by Hayami et al1 during a search for mouse orthologs of the Fc receptor for immunoglobulin A (IgA). PIR-A and PIR-B are not IgA receptors, but have since been characterized as orthologs of the human leukocyte immunoglobulin-like receptors (LILRs); PIR-B has 6 Ig-like domains and 4 immunoreceptor tyrosine-based inhibitory motifs (ITIMs), binds to MHC class I ligands, and typically serves to diminish cellular activation.2,3 The finding that eosinophils express PIR-B is in and of itself not particularly surprising, as PIR-B has already been detected on the surface of mast cells, macrophages, and neutrophils. Similarly unsurprising is the finding that eosinophils isolated from PIR-B gene-deleted mice are effectively “unleashed,” and display augmented responses to the chemoattractant eotaxin-1 both in vitro and in vivo. However, rather more remarkable are the observations that eosinophils (and neutrophils) from the same PIR-B gene-deleted mice display diminished responses to the stimulatory ligand LTB4, and that eosinophil accumulation is reduced in response to chitin and thioglycolate, both stimuli that elicit chemotaxis at least in part based on responses to LTB4. The first question is, of course: what are the molecular mechanisms underlying this original and unexpected finding? Moreover, how does a molecule with consensusinhibitory motifs turn around and effectively augment specific cellular inflammatory responses? Is this unusual response unique to the LTB4-BLT1 ligand-receptor pair? In other words, might the PIR-B gene deletion or PIR-B functional blockade have a unique and

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blood 1 5 J U N E 2 0 0 8 I V O L U M E 1 1 1 , N U M B E R 1 2

unexpected impact on BLT1 receptor expression and/or its signal transduction response? Furthermore, there have been no published reports addressing the expression of the paired activating receptor PIR-A in mouse eosinophils, nor is there any information available on

the role of PIR-A in modulating the responses of wild-type and/or PIR-B gene-deleted eosinophils to specific inflammatory stimuli. In summary, Munitz and colleagues present an intriguing and unexpected finding, one that will certainly unleash our intellectual inhibitions as we continue to explore the role of eosinophils together with this class of immunomodulatory cell-surface receptors. Acknowledgment: Ongoing work in Dr Rosenberg’s laboratory is supported by the NIAID Division of Intramural Research. Please address all correspondence to Dr Rosenberg at [email protected]. Conflict-of-interest disclosure: The author declares no competing financial interests. ■ REFERENCES 1. Hayami K, Fukuta D, Nishikawa Y, et al. Molecular cloning of a novel murine cell-surface glycoprotein homologous to killer cell inhibitory receptors. J Biol Chem. 1997;272:73207327. 2. Katz HR. Inhibitory receptors and allergy. Curr Opin Immunol. 2002;14:698-704. 3. Takai T. Paired immunoglobulin-like receptors and their MHC class I recognition. Immunology. 2005;115: 433-440.

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Comment on Hassane et al, page 5654

Targeting LSCs: powering an old tool ---------------------------------------------------------------------------------------------------------------Simona Salati, Ruth M. Risueno, and Mickie Bhatia

McMASTER UNIVERSITY

In this issue of Blood, Hassane and colleagues describe the discovery of new therapeutic agents effective against leukemic initiating cells through an in silico approach, demonstrating the power of collective knowledge deposited in publicly available gene-expression databases. utative leukemic stem cells (LSCs) are thought to play an important role in the pathogenesis of acute myelogenous leukemia (AML), and in disease initiation and relapse.1 This suggests that it may be important to identify therapeutic strategies that specifically target LSCs while maintaining normal hematopoietic stem cells (HSCs). Previously, Guzman et al reported the activity of a natural compound, parthenolide (PTL), as a potent in vitro agent that selectively affects leukemic initiating cells but not normal progenitors.2 In their most recent study, Hassane and colleagues use the gene-expression signature derived from the treatment of primary AML with PTL to search for similar signatures in publicly available gene-expression profiles and thereby identify candidate compounds

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that may have a similar ability to eradicate LSCs. Using this strategy, they identify 2 new agents, celastrol and 4-hydroxy-nonenal (HNE), that can effectively target cell death of bulk AML cells, as well as functional subsets of AML progenitors and cells detected in the surrogate in vivo assay for human LSCs termed severe combined immunodeficiency leukemia-initiating cells (SL-ICs). These agents do not affect hematopoietic progenitors harvested from healthy individuals. The identified chemicals are a diverse set of compounds that mimic the PTL gene-expression signature and share mechanistic targets with PTL, specifically the capacity to inhibit the NF-␬B survival signal and the induction of oxidative stress, also suggesting that these 5423