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Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling.

Medeiros AI, Serezani CH, Lee SP, Peters-Golden M - J. Exp. Med. (2009)

Bottom Line: Moreover, intrapulmonary administration of ACs demonstrated that PGE(2) generated during efferocytosis and acting via EP2 accounts for subsequent impairment of lung recruitment of polymorphonuclear leukocytes and clearance of Streptococcus pneumoniae, as well as enhanced generation of IL-10 in vivo.These results suggest that in addition to their beneficial homeostatic influence, antiinflammatory programs activated by efferocytosis in the lung have the undesirable potential to dampen innate antimicrobial responses.They also identify an opportunity to reduce the incidence and severity of pneumonia in the setting of lung injury by pharmacologically targeting synthesis of PGE(2) or ligation of EP2.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health Systems, Ann Arbor, MI 48109, USA.

ABSTRACT
The ingestion of apoptotic cells (ACs; termed "efferocytosis") by phagocytes has been shown to trigger the release of molecules such as transforming growth factor beta, interleukin-10 (IL-10), nitric oxide, and prostaglandin E(2) (PGE(2)). Although the antiinflammatory actions of these mediators may contribute to the restoration of homeostasis after tissue injury, their potential impact on antibacterial defense is unknown. The lung is highly susceptible to diverse forms of injury, and secondary bacterial infections after injury are of enormous clinical importance. We show that ACs suppress in vitro phagocytosis and bacterial killing by alveolar macrophages and that this is mediated by a cyclooxygenase-PGE(2)-E prostanoid receptor 2 (EP2)-adenylyl cyclase-cyclic AMP pathway. Moreover, intrapulmonary administration of ACs demonstrated that PGE(2) generated during efferocytosis and acting via EP2 accounts for subsequent impairment of lung recruitment of polymorphonuclear leukocytes and clearance of Streptococcus pneumoniae, as well as enhanced generation of IL-10 in vivo. These results suggest that in addition to their beneficial homeostatic influence, antiinflammatory programs activated by efferocytosis in the lung have the undesirable potential to dampen innate antimicrobial responses. They also identify an opportunity to reduce the incidence and severity of pneumonia in the setting of lung injury by pharmacologically targeting synthesis of PGE(2) or ligation of EP2.

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PGE2/EP2 signaling impairs PMN recruitment and promotes in vivo generation of IL-10 in a mouse model of pneumococcal pneumoniae. 106 apoptotic thymocytes were instilled intranasally in WT and EP2−/− mice and, 16 h later, 106 CFU S. pneumoniae were administered intratracheally. (A–C) PGE2 (A), total TGF-β (B), and IL-10 levels (C) were quantified in the supernatant of lung homogenates from animals studied in Fig. 4 (C and E). (D) PMNs in BALF from WT and EP2−/− mice were counted. Results represent the mean ± SEM of one experiment representative of two (A–C) or of one experiment (D). The number of animals analyzed in each group is indicated above each bar. *, P < 0.05 versus control; #, P < 0.05 versus AC.
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fig5: PGE2/EP2 signaling impairs PMN recruitment and promotes in vivo generation of IL-10 in a mouse model of pneumococcal pneumoniae. 106 apoptotic thymocytes were instilled intranasally in WT and EP2−/− mice and, 16 h later, 106 CFU S. pneumoniae were administered intratracheally. (A–C) PGE2 (A), total TGF-β (B), and IL-10 levels (C) were quantified in the supernatant of lung homogenates from animals studied in Fig. 4 (C and E). (D) PMNs in BALF from WT and EP2−/− mice were counted. Results represent the mean ± SEM of one experiment representative of two (A–C) or of one experiment (D). The number of animals analyzed in each group is indicated above each bar. *, P < 0.05 versus control; #, P < 0.05 versus AC.

Mentions: We next sought to address the impact of PGE2/EP2 signaling on lung levels of antiinflammatory mediators. TGF-β has previously been implicated as an important antiinflammatory mediator in the lung in vivo (6). We verified that lung homogenate TGF-β and IL-10 levels were indeed dose-dependently increased 16 h after the administration of thymocytes in uninfected WT mice. In contrast, levels of NO2− (the stable oxidized derivative of nitric oxide) were unchanged (unpublished data). As expected, PGE2 levels in lung homogenates of infected animals were increased after administration of ACs (Fig. 5 A). S. pneumoniae infection in WT mice increased lung homogenate levels of TGF-β and NO2− but not IL-10 (unpublished data). In this experimental context, administration of ACs had no effect on lung levels of either NO2− or TGF-β (Fig. 5 B) but significantly increased levels of IL-10 (Fig. 5 C). This increase in IL-10 generation after AC administration was not seen in EP2−/− animals (Fig. 5 C). These studies show that PGE2/EP2 signaling drives the enhanced IL-10 production associated with efferocytosis in vivo.


Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling.

Medeiros AI, Serezani CH, Lee SP, Peters-Golden M - J. Exp. Med. (2009)

PGE2/EP2 signaling impairs PMN recruitment and promotes in vivo generation of IL-10 in a mouse model of pneumococcal pneumoniae. 106 apoptotic thymocytes were instilled intranasally in WT and EP2−/− mice and, 16 h later, 106 CFU S. pneumoniae were administered intratracheally. (A–C) PGE2 (A), total TGF-β (B), and IL-10 levels (C) were quantified in the supernatant of lung homogenates from animals studied in Fig. 4 (C and E). (D) PMNs in BALF from WT and EP2−/− mice were counted. Results represent the mean ± SEM of one experiment representative of two (A–C) or of one experiment (D). The number of animals analyzed in each group is indicated above each bar. *, P < 0.05 versus control; #, P < 0.05 versus AC.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2626688&req=5

fig5: PGE2/EP2 signaling impairs PMN recruitment and promotes in vivo generation of IL-10 in a mouse model of pneumococcal pneumoniae. 106 apoptotic thymocytes were instilled intranasally in WT and EP2−/− mice and, 16 h later, 106 CFU S. pneumoniae were administered intratracheally. (A–C) PGE2 (A), total TGF-β (B), and IL-10 levels (C) were quantified in the supernatant of lung homogenates from animals studied in Fig. 4 (C and E). (D) PMNs in BALF from WT and EP2−/− mice were counted. Results represent the mean ± SEM of one experiment representative of two (A–C) or of one experiment (D). The number of animals analyzed in each group is indicated above each bar. *, P < 0.05 versus control; #, P < 0.05 versus AC.
Mentions: We next sought to address the impact of PGE2/EP2 signaling on lung levels of antiinflammatory mediators. TGF-β has previously been implicated as an important antiinflammatory mediator in the lung in vivo (6). We verified that lung homogenate TGF-β and IL-10 levels were indeed dose-dependently increased 16 h after the administration of thymocytes in uninfected WT mice. In contrast, levels of NO2− (the stable oxidized derivative of nitric oxide) were unchanged (unpublished data). As expected, PGE2 levels in lung homogenates of infected animals were increased after administration of ACs (Fig. 5 A). S. pneumoniae infection in WT mice increased lung homogenate levels of TGF-β and NO2− but not IL-10 (unpublished data). In this experimental context, administration of ACs had no effect on lung levels of either NO2− or TGF-β (Fig. 5 B) but significantly increased levels of IL-10 (Fig. 5 C). This increase in IL-10 generation after AC administration was not seen in EP2−/− animals (Fig. 5 C). These studies show that PGE2/EP2 signaling drives the enhanced IL-10 production associated with efferocytosis in vivo.

Bottom Line: Moreover, intrapulmonary administration of ACs demonstrated that PGE(2) generated during efferocytosis and acting via EP2 accounts for subsequent impairment of lung recruitment of polymorphonuclear leukocytes and clearance of Streptococcus pneumoniae, as well as enhanced generation of IL-10 in vivo.These results suggest that in addition to their beneficial homeostatic influence, antiinflammatory programs activated by efferocytosis in the lung have the undesirable potential to dampen innate antimicrobial responses.They also identify an opportunity to reduce the incidence and severity of pneumonia in the setting of lung injury by pharmacologically targeting synthesis of PGE(2) or ligation of EP2.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health Systems, Ann Arbor, MI 48109, USA.

ABSTRACT
The ingestion of apoptotic cells (ACs; termed "efferocytosis") by phagocytes has been shown to trigger the release of molecules such as transforming growth factor beta, interleukin-10 (IL-10), nitric oxide, and prostaglandin E(2) (PGE(2)). Although the antiinflammatory actions of these mediators may contribute to the restoration of homeostasis after tissue injury, their potential impact on antibacterial defense is unknown. The lung is highly susceptible to diverse forms of injury, and secondary bacterial infections after injury are of enormous clinical importance. We show that ACs suppress in vitro phagocytosis and bacterial killing by alveolar macrophages and that this is mediated by a cyclooxygenase-PGE(2)-E prostanoid receptor 2 (EP2)-adenylyl cyclase-cyclic AMP pathway. Moreover, intrapulmonary administration of ACs demonstrated that PGE(2) generated during efferocytosis and acting via EP2 accounts for subsequent impairment of lung recruitment of polymorphonuclear leukocytes and clearance of Streptococcus pneumoniae, as well as enhanced generation of IL-10 in vivo. These results suggest that in addition to their beneficial homeostatic influence, antiinflammatory programs activated by efferocytosis in the lung have the undesirable potential to dampen innate antimicrobial responses. They also identify an opportunity to reduce the incidence and severity of pneumonia in the setting of lung injury by pharmacologically targeting synthesis of PGE(2) or ligation of EP2.

Show MeSH
Related in: MedlinePlus