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(Journal of Leukocyte Biology. 2002;71:966-972.)
© 2002 by Society for Leukocyte Biology

Pulmonary eosinophilia in mice devoid of interleukin-5

Joseph B. Domachowske*, Cynthia A. Bonville*, Andrew J. Easton{dagger} and Helene F. Rosenberg{ddagger}

* Department of Pediatrics, SUNY Upstate Medical University, Syracuse, New York;
{dagger} Department of Biology, University of Warwick, Coventry, United Kingdom; and
{ddagger} Eosinophil Pathoplysiology Section, Laboratory of Host Defenses, NIAID, NIH, Bethesda, Maryland

Correspondence: Helene F. Rosenberg, M.D., Senior Investigator and Head, Eosinophil Pathophysiology Section, LHD/NIAID/NIH, 9000 Rockville Pike, Bethesda, MD 20892. E-mail: hr2k{at}nih.gov


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ABSTRACT
 
The biology of the eosinophilic leukocyte—development, recruitment, and prolonged existence in somatic tissues—has been linked almost invariably to the actions of the "eosinophil" cytokine, interleukin-5 (IL-5). Here we demonstrate that pulmonary eosinophilia can occur in the absence of IL-5, as morphologically normal eosinophils are recruited to the lungs of virus-infected IL-5 -/- mice with kinetics and sequelae that are indistinguishable from those of their IL-5 +/+ counterparts. We conclude that pulmonary eosinophilia observed in response to primary paramyxovirus infection occurs via mechanisms that are distinct from those involved in eosinophil responses to allergens and in asthma. Furthermore, the presence of functional eosinophils in IL-5 -/- mice suggests the possibility of developmentally distinct subsets of what has been presumed to be a homogeneous leukocyte population.


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INTRODUCTION
 
Eosinophilic leukocytes hold an unusual position in mammalian physiology, as they play prominent roles in promoting pathophysiologic conditions such as asthma and respiratory allergies, yet their roles in beneficial, health-promoting events remain poorly understood [1 2 3 4 ]. Our studies regarding the evolution and function of eosinophils and their secretory ribonucleases [5 6 7 ] have led us to consider a role for eosinophils in host defense against single-stranded RNA viruses of the family Paramyxoviridae, including the clinically important human pneumovirus pathogen, respiratory syncytial virus (RSV). To evaluate the antiviral function of eosinophils in vivo, we have used the related natural rodent pathogen, pneumonia virus of mice (PVM), which, when inoculated at low titer, results in a clinical and biochemical syndrome resembling the severe form of human RSV infection. The pulmonary inflammatory response to PVM includes a peak eosinophilia, with eosinophils representing 10–30% of the total cells recruited [8 , 9 ].

The generation of pulmonary eosinophilia has been linked almost invariably to the production of the "eosinophil" cytokine, interleukin-5 (IL-5). While there has been some controversy as to the relative importance of serum as opposed to lung concentrations [10 11 12 ], studies with antibody ablation and with IL-5 -/- gene-deleted mice have shown IL-5 to be a crucial factor contributing to eosinophil recruitment to the lung in response to respiratory allergens and as part of the pathophysiology of asthma [13 14 15 16 17 ]; specific anti-IL-5 therapies have become a major focus of investigation [18 , 19 ]. IL-5 has also been implicated in eosinophilopoesis [20 ], although IL-5-deficient and IL-5 receptor-deficient mice have normal or nearly normal numbers of eosinophils in peripheral blood [16 , 21 ].

In this work, our intent was to evaluate the role of IL-5 in promoting pulmonary eosinophilia observed in response to viral infection by studying the responses of IL-5 gene-deleted mice [16 ]. Among our conclusions, we determined that IL-5 is in fact not a crucial mediator of pulmonary eosinophilia observed in response to respiratory virus infection. The implications of this finding are considered.


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MATERIALS AND METHODS
 
Mouse and virus stocks
All experiments were performed on 6- to 8-week-old IL-5 -/- C57black/6Kopf/tm-1, obtained directly or via breeding pairs from Jackson Laboratories (Bar Harbor, ME) and confirmed as gene-deleted by specific polymerase chain reaction assay [16 ] with C57black/6 wild-type controls. Mice were subjected to brief anaesthesia and were inoculated intranasally with 200 plaque-forming units (pfu) mouse-passaged PVM (strain J3666) or 2000 pfu mouse-passaged Sendai virus [SV; strain 52, American Type Culture Collection (ATCC), Manassas, VA] in an 80 µl volume of Iscove’s modified Dulbecco’s medium (IMDM) on day 0 as described previously [8 , 9 ]. All animal procedures were approved by the NIAID Animal Care Committee (Bethesda, MD), protocol #LHD8E.

Bronchoalveolar lavage (BAL) and differential cell counts from BAL fluid
At time points indicated, mice were sacrificed by cervical dislocation (three mice per condition per time point), and BAL fluid was harvested by trans-tracheal instillation and retrieval of prechilled phosphate buffered saline with 0.25% bovine serum albumin (BSA; 2x0.80 ml instillation with recovery of 1.2–1.5 ml per mouse). Total and differential leukocyte counts were obtained by microscopic evaluation and quantitative analysis of methanol-fixed cytospin preparations stained with Diff Quik (Fisher Scientific, Pittsburgh, PA). We have found BAL analysis to be superior to parenchymal counts in this instance, as eosinophils in PVM-infected mouse lungs are located in small patches and are not spread out smoothly throughout the parenchyma. As such, the values obtained from examining individual sections can vary substantially. Conclusions from the three comparative studies cited in the literature suggest that even under less difficult circumstances, the differences in BAL versus parenchymal analysis, if any, relate to kinetics in hours, not days, and that overall, BAL fluid is a good reflection of the parenchymal leukocyte load [22 23 24 ].

Peripheral blood leukocytes (PBL)
Whole blood was harvested into heparanized syringes via cardiac puncture of anaesthetized mice. Total and differential counts were scored on methanol-fixed, Diff Quik-stained, cytospin slides prepared after red blood cell lysis (ACK lysis buffer, BioWhittaker, Walkersville, MD). Routine differential counts were scored on 100–200 cells per mouse; for eosinophil counts, 150,000–650,000 cells per mouse were surveyed.

Lung homogenates, chemokine, and plaque assays
Mice were killed as described, and lungs were transferred under aseptic conditions into 1 ml prechilled IMDM. Lung tissue was subjected to blade homogenization (Tissumizer, Tekmar, Cincinnati, OH), and cellular debris was removed by low-speed centrifugation. Clarified supernatants were flash-frozen in dry ice-ethanol and were stored at -80°C or liquid nitrogen prior to evaluation. Assays for murine macrophage-inflammatory protein-1{alpha} (MIP-1{alpha}), eotaxin, IL-3, granulocyte macrophage-colony stimulating factor (GM-CSF), and IL-5 were performed per the manufacturer’s instructions (R&D Systems, Minneapolis, MN; limits of detection, 5, 10, 8, 8, and 10 pg/ml, respectively). Results were corrected for total protein as determined by the Bradford assay with BSA standards. Virus recovery was determined by standard plaque assay on BS-C-1 or BHK-21 cell lines (ATCC).

Western blotting
Lanes loaded with 50 µg total lung protein were subjected to reducing-denaturing gel electrophoresis on 14% acrylamide tris-glycine gels, and proteins were transferred to a nitrocellulose membrane by standard methods. Blots were probed with a 1:500 dilution of polyclonal rabbit anti-PVM N protein (recombinant) followed by a 1:1000 dilution of alkaline-phosphatase-conjugated goat anti-rabbit immunoglobulin G (IgG; BioRad, Richmond, CA) and were developed with 5-bromo-4-chloro-3-indolyl phosphate and nitroblue tetrazolium.

Indirect immunofluorescence staining
Rabbit polyclonal anti-mouse eosinophil ribonuclease-2 (mEAR-2) was prepared by standard procedures using baculovirus-derived recombinant protein [25 ] as antigen. Indirect immunofluorescence staining was performed on methanol-fixed goat serum-blocked cytospin preparations of BAL cells using a 1:100 dilution of anti-mEAR-2 followed by a 1:750 dilution of TRITC-conjugated goat anti-rabbit IgG (Pierce Chemical Co., Indianapolis, IN).

Statistical analyses
All data points represent the average ± SE from three mice, and each complete experiment was repeated at least once. Average SE one- and two-tailed, unpaired t-tests were per the algorithms within Microsoft Excel/Microsoft Office NT software.


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RESULTS
 
Cellular inflammatory response to acute paramyxovirus infection
Quantitative analysis of cells in BAL fluid obtained from mice inoculated with 200 pfu PVM or 2000 pfu SV is shown in Table 1 As described previously [8 , 9 ], mice respond to acute PVM infection with rapid accumulation of neutrophilic and eosinophilic granulocytes with as many as 105 leukocytes per ml BAL fluid, detected as early as 3 days after inoculation. In the experiments described here, peak eosinophilia in response to PVM was observed on day 3 with 32 ± 6.2 x 102 eosinophils per ml or 12% of total leukocytes in this sample from IL-5 +/+ mice versus 27 ± 4.4 x 102 eosinophils per ml or 11% of the total leukocytes in the sample obtained from IL-5 -/- mice. Eosinophil counts remained statistically indistinguishable from one another through day 5, after which the eosinophil numbers fall below detectable limits. Pulmonary eosinophilia is also observed in response to SV (Table 1) , a natural rodent paramyxovirus pathogen most closely related to the human pathogen parainfluenza virus I. Similar to the response to PVM, BAL eosinophil counts in SV-infected IL-5 +/+ and IL-5 -/- mice remained statistically indistinguishable from one another, falling below detectable limits on day 5 in response to this inoculum.


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  		Table 1. Eosinophils and Total Leukocytes in BAL Fluid

Detection of proinflammatory mediators in lung tissue
In earlier work, we demonstrated that the acute, cellular, inflammatory response to PVM was dependent on local production of the proinflammatory chemokine MIP-1{alpha} and signaling via its major receptor CCR1 [9 ]. We demonstrate here that local production of MIP-1{alpha} proceeds indistinguishably in IL-5 +/+ versus IL-5 -/- mice; MIP-1{alpha} was not detected in lungs prior to inoculation, but gradually increased in response to infection to levels of 100–200 pg/ml/mg lung tissue by day 5 (Table 2 ). MIP-1{alpha} is also produced in response to infection with SV and was detected at indistinguishable levels in IL-5 +/+ versus IL-5 -/- mice on days 3–5 post-inoculation (unpublished results). In contrast, eotaxin was detected in lung tissue prior to inoculation with PVM, with levels remaining constant throughout the course of infection in both strains of mice. Among other eosinophil-active cytokines, no IL-3 was detected during the course of PVM infection in either strain of mice, and only trace quantities of GM-CSF were detected in PVM-infected lung tissue from IL-5 -/- and IL-5 +/+ mice at the latest stages of infection after resolution of peak eosinophilia.


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  		Table 2. Detection of Proinflammatory Mediators in Lung Tissue Homogenates from PVM-Infected IL5 +/+ and IL5 -/- Mice

Detection of IL-5 in lung tissue
No IL-5 was detected in lung tissue homogenates (Table 3 ) or in serum (unpublished results) from IL-5 +/+ or IL-5 -/- mice evaluated before and during the course of PVM infection. In contrast, IL-5 +/+ mice respond to SV infection with local production of small but significant amounts of IL-5, observed here on days 4 and 5 post-inoculation. As expected, no IL-5 was detected in lung tissue of SV-infected IL-5 -/- mice. It is interesting that the eosinophilia observed in response to SV infection appears to have no relation to the IL-5 produced: The IL-5 production begins as the eosinophilia is resolving with no additional eosinophil responses detected. The eosinophilia observed in response to SV also proceeds unabated in the IL-5 -/- mice.


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  		Table 3. Detection of Interleukin-5 in Lung Tissue Homogenates from PVM- and SV-Infected IL5 +/+ and IL5 -/- mice

PBL
IL-5 +/+ and IL-5 -/- mice respond to PVM infection with a three- to fivefold increase in total leukocytes in peripheral blood, with significant increases observed in the number and percentage of peripheral blood granulocytes (Table 4 ). The total PBL count in IL-5 -/- mice on day 4 (22.7±3.7x103/µl blood) was lower than the PBL count in IL-5 +/+ mice (44.1±2.5x103/µl blood, P<0.0001); the significance of this observation remains unclear. The fraction of eosinophils in the peripheral blood remained low (<0.1%) throughout, with no significant differences in eosinophil number observed between the two strains of mice. A small expansion of the peripheral blood eosinophil population is observed in both IL-5 +/+ and IL-5 -/- strains (Table 5 ).


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  		Table 4. Total Leukocyte (wbc) and Differential Counts in Blood of IL-5 +/+ versus IL-5 -/- Mice


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  		Table 5. Total Leukocyte (wbc) and Eosinophil (Eo) Counts in Peripheral Blood of IL-5 +/+ versus IL-5 -/- Mice

Microscopic evaluation of eosinophils recruited to the lungs of PVM-infected IL-5 -/- mice
A tissue section from lung of an IL-5 -/- mouse on day 3 post-inoculation is shown in Figure 1A , depicting the profound, inflammatory response characteristic of PVM infection in mice. The boxed area is enlarged in Figure 1B to demonstrate the presence of morphologically normal eosinophils (arrows) in the lung tissue. A BAL eosinophil from an IL-5 -/- mouse is shown in Figure 1C , demonstrating the bilobed, annular nucleus and deeply staining, coarsely granulated cytoplasm typical of this cell type in mice. The BAL eosinophil in Figure 1D is stained by indirect immunofluorescence with a polyclonal antibody directed against mEAR-2, a secondary eosinophil granule protein [26 ].



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  		Figure 1. (A) Hematoxylin and eosin-stained lung tissue harvested on day 3 post-inoculation of IL-5 -/- mice with 200 pfu PVM; original magnification, 40x. (B) The region within the box is shown at higher magnification; arrows indicate eosinophils. (C) Granulocytes (neutrophils and eosinophil, at arrow) in BAL fluid from PVM-infected IL-5 -/- mice. (D) Eosinophil from BAL fluid immunofluorescence-stained with anti-mEAR2.

Sequelae of virus infection
In previous work, we and others [6 , 7 , 23 , 27 28 29 ] have documented the antiviral properties of human eosinophils and the eosinophil ribonucleases, eosinophil-derived neurotoxin/RNase 2 and eosinophil cationic protein/RNase 3. We have also shown that gene-deleted mice that are unable to generate granulocytic inflammation respond to PVM infection with enhanced rates of viral replication [9 ]. In this study, with IL-5 +/+ and IL-5 -/- mice, both strains are capable of generating pulmonary eosinophilia in response to PVM infection, and we find that detection of immunoreactive virus in (Fig. 2A ) and recovery of infections virions from (Fig. 2B) lung tissue and mortality rates (Fig. 2C) are indistinguishable from one another.



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  		Figure 2. (A) Detection of immunoreactive PVM in lung homogenates from IL-5 +/+ and IL-5 -/- mice on days 0 (prior to inoculation)–5, as indicated. Shown is a Western blot probed with polyclonal antibody specific for PVM N protein. (B) Recovery of infectious PVM from lung homogenates of IL-5 +/+ and IL-5 -/- mice on days 3–5 post-inoculation, as determined by standard plaque assay on BS-C-1 epithelial cells. (C) Survival of IL-5 +/+ and IL-5 -/- mice inoculated with 10 pfu PVM on day 0.


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DISCUSSION
 
We show here that eosinophils can be recruited to lung tissue in the absence of IL-5, as pulmonary eosinophilia observed in response to infection with the murine paramyxoviruses PVM and SV proceeds normally in mice devoid of this cytokine. Although the extent and kinetics of this response differ somewhat from the eosinophilias observed in allergic conditions, this is not surprising given our conclusions from this work—specifically, that eosinophils are recruited to the lung in response to respiratory virus infection via pathways that are clearly distinct from those related to respiratory allergens, asthma, and parasitic infection. It is interesting that ablation of IL-5-mediated signaling has led to a more sophisticated understanding of the role of IL-5 and eosinophils in the pathogenesis of parasitic infection and its sequelae [30 ]. Furthermore, ablation of IL-5 signaling alone may not achieve complete elimination of the eosinophilic inflammation associated with asthma [25 ]; recent studies demonstrate the persistence of pulmonary eosinophilia in response to allergen challenge in IL-5 -/- BALB/c mice (P. S. Foster, personal communication). This finding may have some relevance to the relatively unimpressive, clinical responses observed in therapeutic trials of anti-IL-5 agents [31 ].

There is a great deal of confusion in the literature regarding the role of eosinophils in paramyxovirus infection. Much of this confusion relates to interpretation of information derived from various mouse models under study. The most familiar model involves the study of mice that are presensitized to virions or virion components and are then challenged with intranasal inoculation of RSV [32 ]. This is a model of acquired immunity, which has shed much light on the unexpected reactions that resulted in the 1960s’ vaccine trial tragedies. For the study of acute inflammatory responses of naïve mice to primary infection or innate immunity, we have developed a new mouse model using PVM, a virus of the same family (Paramyxoviridae) and subfamily (pneumovirinae) as RSV and closest known phylogenetic relative. PVM is a natural pathogen of mice and, when inoculated in quantities as small as 30 pfu, replicates the signs and symptoms of the most severe forms of RSV in humans [8 , 9 ]. We have proceeded in this direction because RSV is not a mouse pathogen and elicits at best a limited, abortive infection with little to no virus replication in lung tissue even in response to a massive, nonphysiologic inoculum of virus particles (>107/mouse). While inflammatory responses to inoculation with high-titer RSV have been shown [33 34 35 ], these are not necessarily innate responses to an RSV infection. Given the limitations of this model, they are more likely to be innate inflammatory responses elicited by a large bolus of foreign antigens that just happen to be viral in origin. Virus infection and foreign antigen reactions are two completely different pathophysiologic phenomena, and each involves unique signaling and response pathways.

While MIP-1{alpha} signaling via its receptor CCR1 is crucial for recruiting eosinophils to the lung in response to virus infection, the timing of MIP-1{alpha} production suggests that the presence of MIP-1{alpha} alone is not a sufficient stimulus for eosinophil recruitment. Although eotaxin levels do not increase in response to viral infection, suggesting that eotaxin is also unlikely to be the primary eosinophil chemoattractant, we cannot rule out the possibility of an interplay or synergy between increasing concentrations of MIP-1{alpha} and constant levels of eotaxin, analogous to what has been described for eotaxin and IL-5 [10 , 36 ].

Our finding that phenotypically normal eosinophils can be elicited in response to a physiologic stimulus in an environment completely devoid of IL-5 suggests that there may be developmentally distinct subsets of eosinophils, including those with IL-5-dependent and IL-5-independent responses and activities. This hypothesis was considered by Kopf and colleagues [16 ] in their description of then-unpublished data relating to the migration of IL-5 -/- eosinophils to the reproductive tract [37 ]. However, Foster and colleagues [25 ] have reviewed recently the signaling pathways leading to eosinophilia and have concluded that IL-5 is primarily responsible for the allergen-induced expansion of pre-existing bone marrow and peripheral blood eosinophil populations, findings more suggestive of a continuum of function than of distinct eosinophil populations per se. From the perspective of the respiratory system, it is tempting to speculate that IL-5 plays a larger role in the more negative aspects of eosinophil biology, as IL-5 has been implicated not only in eosinophil overproduction, but also in recruitment and prolonged viability of eosinophils in asthmatic and allergic lung tissue. However, we have suggested recently that these IL-5-dependent responses may represent a dysregulation of responses designed to function in antiviral host defense [28 , 29 ]; two recent studies support this hypothesis [38 ]. Further characterization of IL-5-dependent and IL-5-independent eosinophil responses may ultimately provide us with some insight into how one might modulate and regulate the positive and negative features of eosinophils and of the eosinophilic inflammatory response.


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ACKNOWLEDGEMENTS
 
This work was supported in part by a grant from the Sinsheimer Foundation to J. B. D. We thank Ms. Shelley Butler and the staff of the NIAID Building 7 Animal Facility for the care and breeding of the mice used in these experiments.

Received September 20, 2001; revised February 5, 2002; accepted February 11, 2002.


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