Expression of the secondary granule proteins major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX) is required for eosinophilopoiesis in mice

Doyle, Alfred D.; Jacobsen, Elizabeth A.; Ochkur, Sergei I.; McGarry, Michael P.; Shim, Kevin G.; Nguyen, D.T.; Protheroe, Cheryl; Colbert, Dana; Kloeber, Jake A.; Neely, Joseph; Shim, Kelly P.; Dyer, Kimberly D.; Rosenberg, Helene F.; Lee, James J.; Lee, Nancy A.

doi:10.1182/blood-2013-01-473405

Cited by 66 publications

(68 citation statements)

References 42 publications

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“…These findings support the eosinophil as a key player in allergic inflammation and tissue homeostasis in hypersensitivity diseases (1,2). Eosinophil-deficient mouse models (3,4,6), including EDGP gene-deleted mice (7)(8)(9), provide unique insights into the role of the eosinophil, in both tissue damage/repair/remodeling and novel immunomodulatory roles that bridge host innate and adaptive immune responses in allergic and parasitic diseases.…”

supporting

confidence: 61%

“…Knock-out of the EPX gene (EPX Ϫ/Ϫ ) and resulting EPX deficiency had no impact on asthma-associated pulmonary pathologies induced by allergen sensitization and provocation (39), suggesting that the contributions of MBP-1 and EPX to disease pathology in allergic diseases likely occurred via their combined activities. Crossing MBP-1 Ϫ/Ϫ and EPX Ϫ/Ϫ knock-out mice to address this issue in double knockouts unexpectedly generated a novel strain of mice with a highly specific deficiency in eosinophilopoiesis, and therefore eosinophils (9). Although the mechanism for the eosinophil deficiency in these double knock-out mice remains to be determined, results suggest that: (i) granule protein gene expression and/or defective granulogenesis may be a checkpoint for survival of eosinophil progenitors, (ii) loss of concurrent expression of MBP-1 and EPX disrupts lineage-instructive gene regulatory mechanisms required for self-renewal or eosinophil progenitor survival, or (iii) most likely, dysfunctional granulogenesis leads to aberrant intracellular release of a toxicant such as mouse eosinophilassociated ribonucleases (EARs) capable of degrading intracellular RNAs, leading to the observed cell-autonomous defect (39).…”

Section: Eosinophil Major Basic Protein-1mentioning

confidence: 99%

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Eosinophil Granule Proteins: Form and Function

Acharya

Ackerman

2014

Journal of Biological Chemistry

418

364

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Experimental and clinical data strongly support a role for the eosinophil in the pathogenesis of asthma, allergic and parasitic diseases, and hypereosinophilic syndromes, in addition to more recently identified immunomodulatory roles in shaping innate host defense, adaptive immunity, tissue repair/remodeling, and maintenance of normal tissue homeostasis. A seminal finding was the dependence of allergic airway inflammation on eosinophil-induced recruitment of Th2-polarized effector T-cells to the lung, providing a missing link between these innate immune effectors (eosinophils) and adaptive T-cell responses. Eosinophils come equipped with preformed enzymatic and nonenzymatic cationic proteins, stored in and selectively secreted from their large secondary (specific) granules. These proteins contribute to the functions of the eosinophil in airway inflammation, tissue damage, and remodeling in the asthmatic diathesis. Studies using eosinophil-deficient mouse models, including eosinophil-derived granule protein double knock-out mice (major basic protein-1/eosinophil peroxidase dual gene deletion) show that eosinophils are required for all major hallmarks of asthma pathophysiology: airway epithelial damage and hyperreactivity, and airway remodeling including smooth muscle hyperplasia and subepithelial fibrosis. Here we review key molecular aspects of these eosinophil-derived granule proteins in terms of structure-function relationships to advance understanding of their roles in eosinophil cell biology, molecular biology, and immunobiology in health and disease.

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supporting

confidence: 61%

Section: Eosinophil Major Basic Protein-1mentioning

confidence: 99%

Eosinophil Granule Proteins: Form and Function

Acharya

Ackerman

2014

Journal of Biological Chemistry

418

364

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“…In secondary infection, our results indicate that infected MBP -/- and EPO -/- mice were similar to WT mice in resisting secondary infection. It is possible that MBP and EPO are functionally redundant, so that deleting both genes would be required to document their action against NBL in vivo ; however, testing this hypothesis directly is not possible, because MBP and EPO double knockout mice lack eosinophils (60). A recent report documented a requirement for eosinophils in protection against primary, but not secondary infection by Brugia malayi .…”

Section: Discussionmentioning

confidence: 99%

Eosinophils Mediate Protective Immunity against Secondary Nematode Infection

Huang

Gebreselassie

Gagliardo

et al. 2015

The Journal of Immunology

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Eosinophils are versatile cells that regulate innate and adaptive immunity, influence metabolism and tissue repair, and contribute to allergic lung disease. Within the context of immunity to parasitic worm infections, eosinophils are prominent yet highly varied in function. We have shown previously that when mice undergo primary infection with the parasitic nematode, Trichinella spiralis, eosinophils play an important, immune regulatory role that promotes larval growth and survival in skeletal muscle. In this study, we aimed to address the function of eosinophils in secondary infection with T. spiralis. By infecting eosinophil-ablated mice, we found that eosinophils are dispensable for immunity that clears adult worms or controls fecundity in secondary infection. In contrast, eosinophil ablation had a pronounced effect on secondary infection of skeletal muscle by migratory newborn larvae. Restoring eosinophils to previously infected, ablated mice caused them to limit muscle larvae burdens. Passive immunization of naïve, ablated mice with sera or immunoglobulin from infected donors, together with transfer of eosinophils, served to limit the number of newborn larvae that migrated in tissue and colonized skeletal muscle. Results from these in vivo studies are consistent with earlier findings that eosinophils bind to larvae in the presences of antibodies in vitro. Although our previous findings showed that eosinophils protect the parasite in primary infection, these new data show that eosinophils protect the host in secondary infection.

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“…However, it is also noteworthy that these data do not rule out additive or synergistic events that the concurrent loss of both proteins may have on these pathologies following their release from activated eosinophils. Unfortunately, mice with targeted mutations of both granule protein genes display an inherent defect in eosinophilopoiesis that abrogates the production of mature peripheral eosinophils (58). As a result, although it is possible to generate I5/hE2/MBP-1 has nominal but differential effects on the induced histopathologies/remodeling occurring in I5/hE2 mice.…”

Section: Discussionmentioning

confidence: 99%

Lung Pathologies in a Chronic Inflammation Mouse Model Are Independent of Eosinophil Degranulation

Jacobsen

Ochkur

Doyle

et al. 2017

Am J Respir Crit Care Med

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Rationale: The release of eosinophil granule proteins in the lungs of patients with asthma has been dogmatically linked with lung remodeling and airway hyperresponsiveness. However, the demonstrated inability of established mouse models to display the eosinophil degranulation occurring in human subjects has prevented a definitive in vivo test of this hypothesis.Objectives: To demonstrate in vivo causative links between induced pulmonary histopathologies/lung dysfunction and eosinophil degranulation.Methods: A transgenic mouse model of chronic T-helper cell type 2-driven inflammation overexpressing IL-5 from T cells and human eotaxin 2 in the lung (I5/hE2) was used to test the hypothesis that chronic histopathologies and the development of airway hyperresponsiveness occur as a consequence of extensive eosinophil degranulation in the lung parenchyma.Measurement and Main Results: Studies targeting specific inflammatory pathways in I5/hE2 mice surprisingly showed that eosinophil-dependent immunoregulative events and not the release of individual secondary granule proteins are the central contributors to T-helper cell type 2-induced pulmonary remodeling and lung dysfunction. Specifically, our studies highlighted a significant role for eosinophil-dependent IL-13 expression. In contrast, extensive degranulation leading to the release of major basic protein-1 or eosinophil peroxidase was not causatively linked to many of the induced pulmonary histopathologies. However, these studies did define a previously unappreciated link between the release of eosinophil peroxidase (but not major basic protein-1) and observed levels of induced airway mucin.Conclusions: These data suggest that improvements observed in patients with asthma responding to therapeutic strategies ablating eosinophils may occur as a consequence of targeting immunoregulatory mechanisms and not by simply eliminating the destructive activities of these purportedly end-stage effector cells.

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Expression of the secondary granule proteins major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX) is required for eosinophilopoiesis in mice

Abstract: Key Points The loss of the two most abundant eosinophil granule proteins disrupts the production of blood eosinophils from marrow progenitors. Knockout animals deficient for both MBP-1 and EPX represent a novel strain of mice with a specific and congenital loss of eosinophils.

Cited by 66 publications

References 42 publications

Eosinophil Granule Proteins: Form and Function

Eosinophil Granule Proteins: Form and Function

Eosinophils Mediate Protective Immunity against Secondary Nematode Infection

Lung Pathologies in a Chronic Inflammation Mouse Model Are Independent of Eosinophil Degranulation

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