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(Journal of Leukocyte Biology. 2001;69:75-80.)
© 2001 by Society for Leukocyte Biology

Severe exercise enhances phagocytosis by murine bronchoalveolar macrophages

Shu-Hui Su, Hsiun-ing Chen and Chauying J. Jen

Department of Physiology, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan, Republic of China

Correspondence: Dr. Chauying J. Jen, Department of Physiology, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan, Republic of China. E-mail: jen{at}mail.ncku.edu.tw


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Because physical activity affects the immune competency of individuals by an unknown mechanism, we investigated the effect of acute exercise on phagocytosis of bronchoalveolar macrophages (BAMs). Male BALB/c mice, 7–9 weeks old, ran on a treadmill to exhaustion (severe exercise, SE) or at a final speed of 17 m/min for 30 min (moderate exercise, ME). Although both exercise protocols induced differential leukocytosis, 95% leukocytes from lung lavages of both groups were BAMs. The BAM phagocytic capacity of nonopsonized beads increased immediately after SE but not after ME, gradually returning to the basal level after 4 h. SE upregulates the macrophage scavenger receptors (SR-A type I/II and MARCO), CR3, and ICAM-1, but not Fc{gamma}R. Although the blocking effect of MARCO antibody was most pronounced, that of ICAM-1 antibody was totally reversed by cross-linking CR3. Our results showed that SE, but not ME, activated BAMs and that the enhanced nonopsonized phagocytosis was mainly mediated by scavenger receptors and ICAM-1/CR3.

Key Words: scavenger receptor • CR3 • ICAM-1


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is generally believed that physical exercise exerts profound effects on the immune responses. Earlier studies have shown that acute exercise alters the number of circulating leukocytes as well as various functions of lymphocytes, natural killer (NK) cells, and granulocytes [1 , 2 ]. As for tissue macrophages, previous work was focused on the exercise effects on the phagocytic ability of peritoneal macrophages [3 ], showing elevated phagocytosis. Thus, the changes in immune cell number and/or function resulting from exercise may play a role in host resistance to infection.

Epidemiological studies have highlighted the importance of physical activity in relation to the incidence of upper respiratory tract infection [2 , 4 ] and the lower prevalence and mortality rates for various site-specific cancers [5 ]. Whether or how exercise affects lung immunity is an important but still unclear issue. In animal studies, treadmill exercise increases the NK-cell cytotoxic activity and decreases the lung retention of tumor cells [6 7 8 ]. However, even after the depletion of NK cells, animals subjected to exercise still show lower retention of tumor cells [8 , 9 ]. Recent studies demonstrate that exercise increases peritoneal macrophage antitumor cytotoxicity [10 , 11 ]. Therefore, it seems likely that bronchoalveolar macrophages (BAMs) may actively participate in the exercise-enhanced lung immunity.

Acute exercise drastically alters physiological conditions in systemic and pulmonary circulation. It has been shown that the increase of circulating leukocytes depends on the intensity, duration, and type of exercise [12 ]. However, how the lung-immunity status changes after a single exercise session is unclear at the present time. We, therefore, investigated the effects of moderate and severe exercise (ME and SE, respectively) on the function of murine BAMs, the major pulmonary immune cells. BAMs are known to function through a variety of mechanisms, including their abilities to undergo phagocytosis and to express specific cell-surface receptors [13 ]. In this study, we examined the effects of exercise on BAM number, phagocytic capacity, as well as the role of various BAM surface receptors, including scavenger receptors, Fc receptor for immunoglobulin G (IgG; Fc{gamma}R), complement receptor type 3 (CR3), and intercellular adhesion molecule-1 (ICAM-1). Although scavenger receptors and Fc{gamma}R are phagocytosis-related receptors, CR3 and ICAM-1 are usually considered macrophage-activation markers [14 , 15 ].


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Reagents
Carboxylate-modified fluorescent latex beads, bovine serum albumin (BSA), and purified mouse IgG were purchased from Sigma (St. Louis, MO). Rat antimouse CD11b monoclonal antibody (mAb; M1/70) was purchased from PharMingen (San Diego, CA). Protein G-Alexa Fluor 488-conjugate was purchased from Molecular Probes (Eugene, OR). Rat antimouse MARCO (ED31), scavenger receptor I/II (2F8) mAbs, and phycoerythrin (PE) or fluorescein isothiocyanate (FITC)-conjugate of F(ab')2 goat antirat IgG were purchased from Serotec (Oxford, UK). The neutralizing polyclonal antibody against murine ICAM-1 (H-108) was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). All other chemical reagents used in this study were purchased from Merck (Darmstadt, Germany).

Experimental animals and exercise regime
Male BALB/c mice, 7–9 weeks old, were purchased from the National Cheng Kung University Animal Center (Tainan, Taiwan). The mice were divided randomly into three groups, namely sedentary control, ME, and SE. It has been shown that the oxygen consumption of small rodents running on the treadmill can be predicted by their running speed [16 ]. Based on this study, the following exercise protocols were used for mice to achieve ME and SE (about 60% and >80% of maximal oxygen consumption, respectively). The ME group ran on a treadmill starting at 9 m/min for 3 min followed by a 2 m/min increment every 3 min until a speed of 17 m/min was reached. Running was continued for a total duration of 30 min without further increase in speed. The SE group ran in a similar way until a speed of 17 m/min, and thereafter continued to run with 1 m/min increments every 3 min until exhaustion. The SE mice were usually exhausted at 24 m/min with a total running time of about 36 min. To avoid novel effects, the sedentary control mice were placed on the treadmill for 10 min without exercise. The circulating leukocyte count was measured to confirm that different exercise intensities were indeed effective. Immediately after SE or ME, the circulating leukocytes increased to >100% or to about 60%, respectively. This parameter returned to its resting value within 24 h.

Isolation of BAMs
Animals were anesthetized by intraperitoneal injection of 0.1–0.15 ml sodium pentobarbital (50 mg/ml). The BAM isolation procedure was modified from a published method [17 ]. Briefly, murine lungs were filled and flushed five times with 1 ml of prewarmed phosphate-buffered saline (PBS; 145 mM NaCl, 5 mM KCl, 9.35 mM Na2HPO4, 1.9 mM KH2PO4, 5.5 mM glucose, pH 7.4). This procedure was repeated twice for a total vol of about 2 ml of lung lavage per animal. BAMs were collected by centrifugation at 800 g for 8 min at 4°C and were resuspended in PBS. The percentage of BAM in lung lavages was measured using Wright’s differential leukocyte staining. The viability of cells was >98% as revealed by trypan blue exclusion test.

Nonopsonized and opsonized phagocytosis
Carboxylated fluorescent latex microspheres (2 µm in diameter) were coated for 1 h with 1% BSA or 0.2 mg/ml mouse IgG at room temperature, sonicated for 5 min, and thereafter washed twice in PBS. For the preparation of complement-opsonized beads, the IgG-coated beads were incubated further for 1 h with normal mouse serum (fourfold dilution) at room temperature, and then washed twice. The suspensions were adjusted to a final concentration of 3.2 x 106 beads/10 µl PBS. BAMs were incubated for 1 h with the bead suspension (cell:bead=1:30) at 37°C in a divalent cation-containing PBS (0.15 mM CaCl2, 0.1 mM MgCl2, and 0.03 mM MgSO4). Cells were subsequently washed with cold PBS to eliminate uningested particles and were thereafter fixed with 4% paraformaldehyde. The fluorescence histogram of macrophages was measured by a flow cytometer (FACSort, Becton Dickinson, San Jose, CA). Results were presented as population percentage of phagocytic cells or as averaged number of ingested beads per cell (phagocytosis index). Percentage of phagocytic cells = number of macrophage that ingest at least one bead/total number of macrophages x 100. Phagocytosis index = number of ingested beads/total number of macrophages. Additionally, the same BAMs were cytospun and stained after phagocytosis. Adhered and phagocytosed beads were measured by counting the number of cell-associated beads for 200 cells under a 100x oil-immersion objective. Beads were scored as phagocytosed when they were at the same depth of field as the cell. Beads were scored as adhered when they were attached to the cell membrane, either at different depth-of-field compared with the cell or in profile to be outside the cell membrane [18 ].

Immunofluorescence staining and flow cytometry
To examine BAM surface receptors, the cells were incubated for 1 h with various primary antibodies at 4°C. After cold PBS wash, cells were incubated further for 1 h with fluorescence-labeled goat antirat IgG or protein G Alexa Fluor 488-conjugate at 4°C. The BAMs were then washed twice in PBS, fixed with 4% paraformaldehyde, and thereafter analyzed by the flow cytometer.

Statistics
Data were expressed as mean ± SE, and n = number of animals in that group. Results were analyzed by one-way analysis of variance (ANOVA) and considered to be significantly different when P < 0.05. Student-Newman-Keuls contrast procedures were performed when significant main effects were found.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effects of exercise on the number and phagocytosis of collected BAMs
BAMs were the major cell type (95%) collected in all murine lung lavages. Therefore, we used the entire collected leukocyte population as BAMs without further purification. The BAM count was not affected by ME but was reduced immediately after SE and thereafter returned to basal level after 1 h (Table 1 ). We further examined the effect of the exercise regime used on the BAM phagocytosis of BSA-coated beads. BAM with ingested beads were analyzed by flow cytometry or examined under a fluorescence microscope. Although flow cytometry results are more quantitative, microscopic observation allows distinction between phagocytosed beads from adhered beads. In this study, because the adhered beads were only about 2% of cell-associated beads, results obtained from these two methods were consistent and comparable with each other. Figure 1 shows that SE, but not ME, enhanced BAM phagocytosis of nonopsonized beads. It is clear that BAMs with fluorescence intensity below 50 units did not ingest any bead and that each ingested bead contributed to about 100 fluorescence units. The summarized values (n=6) of percentage of phagocytic cells and phagocytosis index were 44.2 ± 5.5% and 1.3 ± 0.5, respectively, for control BAMs, and the values for the SE-treated BAMs were 83.7 ± 5.4% and 4.3 ± 1.1, respectively, and those of ME-treated BAMs were 40.4 ± 3.5% and 1.2 ± 0.3, respectively. The time course of SE-induced BAM phagocytosis of nonopsonized beads is summarized in Figure 2 . The SE-enhanced phagocytosis was most pronounced immediately after exercise and gradually diminished in 4 h.


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  		Table 1. BAM Counts in Sedentary Control and Different Exercise Groups

 


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  		Figure 1. BAM phagocytosis of fluorescently labeled latex beads. Flow cytometric analysis shows BAM phagocytosis of nonopsonized beads. (A) Control, (B) post-SE 0 h, and (C) post-ME 0 h. Percentage of phagocytic cells, %P (i.e., number of cells that ingest at least one bead divided by total cell numbers), and phagocytosis index, PI (total ingested beads/total number of cells), were calculated and are shown next to the respective histogram. (D) The morphology of BAMs that did not ingest any bead (M0) and that ingested one bead (M1), two beads (M2), or numerous beads (Mx) as viewed under light microscope.

 


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  		Figure 2. Effects of SE on BAM phagocytosis. Percentage of phagocytic cells and phagocytosis index were calculated from flow cytometric results. Data are presented as mean ± SE (n=6). One-way ANOVA, *P < 0.05 compared with control and post-SE 4-h values.

 
Opsonin-dependent phagocytosis of BAMs
Generally speaking, the binding of opsonins, including immunoglobulins and complement-like factors, could enhance the clearance of foreign materials by macrophages. Therefore, we also assayed the effect of SE on Fc{gamma}R-mediated and complement receptor-mediated phagocytosis. Results in Figure 3 show that the BAM phagocytic capacity was elevated for opsonin-coated beads. However, the SE effect on phagocytosis of these opsonized beads was minimal, indicating that SE mainly altered BAM phagocytosis of nonopsonized beads.



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  		Figure 3. Effects of SE on BAM phagocytosis of nonopsonized and opsonized beads. Data are presented as mean ± SE (n=4). One-way ANOVA, *P < 0.05 compared with nonopsonized values in the same group, and #P < 0.05 relative to the corresponding control.

 
Role of scavenger receptors in SE-enhanced BAM phagocytosis
To investigate the cellular mechanisms responsible for this SE-enhanced BAM phagocytosis of nonopsonized beads, we examined the possibility of surface-receptor upregulation. Macrophages are known to use scavenger receptors for phagocytosis. The expression of scavenger receptor-A subtype I/II and MARCO on BAM was accessed in this study, and results showed higher expression of both after SE (Table 2 ). Although the MARCO expression was less than SR-A type I/II, the increase of MARCO after SE was more pronounced (162%) than that of type I/II (64%). Functionally, the antibody against MARCO, ED31, eliminated a large portion of SE-induced elevation of phagocytosis (Fig. 4 ). As a comparison, the blocking experiments using antibody 2F8 showed that SR-A type I/II was relatively unimportant in the SE-enhanced BAM phagocytosis. Scavenger receptor-A binds avidly to polyanionic molecules via its charged collagen-like structure [19 ]. Although polyinosinic acid (poly-I) and heparin are polyanions, only poly-I blocks scavenger receptors [20 ]. Our results are consistent with this notion. Figure 4 shows the enhanced poly-I inhibition on BAM phagocytosis in SE compared with control. Heparin, on the contrary, was totally ineffective.


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  		Table 2. Effects of Severe Exercise on the Expression of BAM Surface Receptors

 


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  		Figure 4. Effects of scavenger receptor antibodies and inhibitors on BAM phagocytosis. After a 20-min preincubation with 20 µg/ml ED31 (anti-MARCO), 5 µg/ml 2F8 (anti-type I/II), or 30 µg/ml poly-I or heparin (negative control), the BAM phagocytosis of nonopsonized beads was determined. Percent difference from vehicle was calculated as the reduction of phagocytosis index compared with saline-treated BAMs. Data are presented as mean ± SE (n=4). One-way ANOVA, *P < 0.05 compared with vehicle value in the same group, and #P < 0.05 relative to the corresponding control.

 
SE-induced changes of other surface-receptor expression
In addition, we examined the expression of CR3, or the integrin CD11b/CD18, ICAM-1, and pan Fc{gamma}R on BAMs. As shown in Table 2 , SE increased the BAM surface expression of CR3 (labeled with an antibody against its {alpha} chain CD11b) and ICAM-1 but not Fc{gamma}R. Moreover, the increase in the level of CR3 was diminished gradually in hours (unpublished results). It is interesting to know whether CR3 and ICAM-1 modulate the SE-enhanced BAM phagocytosis. Our results showed that the inhibitory effect of anti-ICAM-1 antibody on BAM phagocytosis was also more pronounced in SE compared with control (Fig. 5A ). Conversely, the anti-CR3 antibody used in this study did not have any neutralizing effect.



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  		Figure 5. The role of ICAM-1 and CR3 in BAM phagocytosis of nonopsonized beads. (A) Effects of neutralizing antibody against ICAM-1 on BAM phagocytosis. After 20 min incubation with antibody (0.1–10 µg/ml) at 4°C, BAMs were incubated further with fluorescently labeled, albumin-coated latex beads, and the phagocytosis index was measured by flow cytometry. Normal mouse IgG was used as control antibody. The percent difference from vehicle was calculated based on the reduction of phagocytosis index by antibody treatment. (B) Interaction between ICAM-1 and CR3. In the presence or absence of 3 µg/ml neutralizing antibody against ICAM-1, BAM-surface CD11b molecules were first cross-linked for 20 min with anti-CD11b antibody at 4°C. BAMs were incubated subsequently for 20 min with a secondary antibody F(ab')2, and their phagocytosis index values were determined. Phagocytosis index values were compared with those obtained in the absence of any antibodies. Data are presented as mean ± SE (n=4). One-way ANOVA, *P < 0.05 compared with the value of combined treatment with anti-ICAM-1 antibody and CD11b cross-linking in the same group.

 
CR3 and ICAM-1 are known to serve as a receptor/counter-receptor pair, and they function cooperatively [21 ]. Therefore, we examined whether cross-linking the receptor CR3 can mimic the interactions between these two receptors. First, the ICAM-1 receptors were blocked by a 10-min preincubation with 3 µg/ml anti-ICAM-1 antibody. Then, the CR3 receptors were cross-linked by sequential addition of anti-CD11b antibody and their secondary antibody. We found that the inhibitory effect of anti-ICAM-1 antibody on phagocytosis could be reversed completely by cross-linking CD11b further. Moreover, cross-linking CD11b without prior blocking of ICAM-1 showed enhanced phagocytosis (Fig. 5B) .


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is the first study demonstrating that acute SE, but not ME, enhanced murine BAM phagocytosis without causing infiltration of other leukocytes into the lungs. The SE-induced phagocytosis elevation in BAMs was most pronounced with respect to the ingestion nonopsonized particles. This SE effect was accompanied by higher expression of scavenger receptors, CR3 and ICAM-1, with MARCO being the most important receptor type involved.

A single bout of strenuous running caused a transient murine BAM phagocytosis elevation as well as a transient decrease in BAM number. Studies using human subjects or animals have shown that exercise affects a wide range of immune parameters [1 , 2 ]. Most notably, acute exercise induces a rapid interchange of leukocytes between peripheral lymphoid tissues and the circulation, as indicated by a biphasic leukocytosis [12 ]. However, we show that there was no obvious infiltration of circulating leukocytes into the lung after SE. It is likely that the decrease in BAM number (collected in the first 2 ml of lavages) immediately after SE may result from the stronger adhesion between BAM and epithelium and/or a deeper movement of BAM into the lower airway. We have collected BAMs from additional lung flushed, up to 6 ml of lavages, and found no difference in total BAM number between control and exercised animals (unpublished results). Moreover, these BAMs from SE group also showed elevated phagocytic capacity. Therefore, all BAMs collected were apparently activated during SE and were more phagocytic.

Although the detail cause of exercise-induced lung immunity alteration cannot be investigated thoroughly in a single study, our results clearly show that SE, but not ME, enhances BAM phagocytosis. Various stress hormones and cytokines are known to be elevated in response to different exercise protocols [2 ]. One would assume that once the threshold of a certain hormone or cytokine is reached, BAMs become stimulated. However, the exercise effects are most likely to be more complicated than this assumption. Not only do these hormones and cytokines interact with one another, but also the exercise effects on certain physiological parameters can be in different directions as dictated by the exercise intensities. Our previous study showed the different effects between these two exercise intensities on platelet function in humans, where ME was found to inhibit platelets, and SE activated them [22 ].

Of all immune cells, NK cells, neutrophils, and macrophages (of the innate system) appear to be most responsive to acute exercise, in terms of cell number and function [3 , 11 ]. Several studies have demonstrated that exercise increases the antitumor cytotoxicity of alveolar and peritoneal macrophages [6 , 10 , 11 ]. Resident macrophages are the first line of defense against microbial invaders and malignancies by virtue of their phagocytic, cytotoxic, and intracellular killing capacity. Therefore, the growth reduction of site-specific tumors, especially in the lungs [6 , 23 ], by exercise could be partially attributed to the elevated phagocytosis of macrophages. In the lung, SE may be beneficial to cytolysis of tumor cell but not to the viral infection [24 ]. The latter effect of SE may be attributed to the suppression of macrophage-antigen presentation [25 ]. Although SE might not affect different pathogenic infections equally, the SE-enhanced phagocytosis of nonopsonized particles should lead to a faster clearance of foreign pathogens in general and decrease the possibility of acute lung injury.

Our results indicated that the SE effect on BAMs was most pronounced with regard to nonopsonized phagocytosis and that this effect was likely mediated by elevated scavenger receptors (especially MARCO) and CR3/ICAM-1 on their surface. Whether the exercise-enhanced phagocytic activity is generally mediated by the modulation of surface receptors in immune cells is an interesting question. The scavenger receptor class A has been shown to mediate the ingestion of nonopsonized latex beads, environmental particles, and certain bacteria [19 , 26 , 27 ]. These scavenger receptors may thus play a major role in safeguarding against large amounts of airborne particles, which are likely to be encountered during severe exercise. To our knowledge, the possible exercise effects on macrophage scavenger receptors have not been shown before. Results from this study have confirmed that the scavenger receptor-A is constitutively expressed in murine BAMs [28 ]. In addition, we demonstrated that SR-A type I/II were the major subtypes (Table 2) . It is interesting that although MARCO was relatively sparse on control BAM surface, this scavenger receptor subtype was largely upregulated after SE and appeared to play an important role in the SE-enhanced BAM phagocytosis. Conversely, the interaction of BAM activation markers, CR3 and ICAM-1, may also play a role in the SE effect because both receptors were upregulated as well. Previous studies have shown that severe exercise causes elevated expression of CR3 in circulating granulocytes [29 30 31 ] and also of ICAM-1 in monocytes [32 ]. In contrast, moderate exercise leads to decreased expression of ß1 and ß2 integrins in leukocytes [33 ].

In this study, we showed that BAM phagocytosis was suppressed by blocking ICAM-1 and that this suppression was reversed by cross-linking CD11b (Fig. 5) . This finding suggests that ICAM-1 may affect phagocytosis via its counter-receptor CR3 by outside-in signaling in the same cell type. In general, these two receptors are expressed in different cell types, for instance CR3 on leukocytes and ICAM-1 on endothelial/epithelial cells, for the mediation of leukocyte adhesion and extravasation. The stimulatory effects of ICAM-1 on BAM phagocytosis [34 ] and cytokine production [35 ] are probably mediated by the surface ß2 integrin family including CR3. When CR3 but not other ß2 integrins is cross-linked with specific antibodies to either one of its subunits (CD11b or CD18), it can trigger intracellular tyrosine phosphorylation [36 ]. Besides, CR3 can serve as signaling partners for other receptors or cytokines to induce a synergistic activation of macrophage [21 , 37 ].

In summary, acute SE, but not ME, increases murine BAM phagocytic capacity. This exercise effect is likely mediated by the upregulation of BAM surface receptors. However, we cannot rule out the possible participation of other factors, such as cytokine levels and pulmonary surfactant amount/composition, which also change during physical exercise.


   ACKNOWLEDGEMENTS
 
This study was funded by grants from National Science Council and National Health Research Institute, Taiwan, Republic of China, grant numbers NSC 89-2320-B-006-045, NSC 89-2320-B-006-046, and NHRI-GT-EX8989S834L. The authors are indebted to the helpful discussions from Drs. H. Y. Lei and K. L. Chang and to the critical reading of the manuscript from Dr. H. Essackjee.

Received June 12, 2000; revised August 30, 2000; accepted August 31, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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S.-H. Su, H.-i. Chen, and C. J. Jen
C57BL/6 and BALB/c Bronchoalveolar Macrophages Respond Differently to Exercise
J. Immunol., November 1, 2001; 167(9): 5084 - 5091.
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