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Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus
Ana Cg Salina1, Tais P Souza1, Carlos H Serezani2
11 Department of Biological Science, School of Pharmaceutical Science, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil.
Abstract:
Alveolar macrophages (AMs) are multitasking cells that maintain lung homeostasis by clearing apoptotic cells (efferocytosis) and performing antimicrobial effector functions. Different PRRs have been described to be involved in the binding and capture of non-opsonized Streptococcus pneumoniae, such as TLR-2, mannose receptor (MR) and scavenger receptors (SRs). However, the mechanism by which the ingestion of apoptotic cells negatively influences the clearance of non-opsonized S. pneumoniae remains to be determined. In this study, we evaluated whether the prostaglandin E2 (PGE2) produced during efferocytosis by AMs inhibits the ingestion and killing of non-opsonized S. pneumoniae. Resident AMs were pre-treated with an E prostanoid (EP) receptor antagonist, inhibitors of cyclooxygenase and protein kinase A (PKA), incubated with apoptotic Jurkat T cells, and then challenged with S. pneumoniae. Efferocytosis slightly decreased the phagocytosis of S. pneumoniae but greatly inhibited bacterial killing by AMs in a manner dependent on PGE2 production, activation of the EP2-EP4/cAMP/PKA pathway and inhibition of H2O2 production. Our data suggest that the PGE2 produced by AMs during efferocytosis inhibits H2O2 production and impairs the efficient clearance non-opsonized S. pneumoniae by EP2-EP4/cAMP/PKA pathway.
Insights
Alveolar macrophages performing efferocytosis produce prostaglandin E2 (PGE2), which impairs bacterial killing. This PGE2-mediated inhibition of Streptococcus pneumoniae clearance involves the EP2-EP4/cAMP/PKA pathway.
Area of Science:
- Immunology
- Cell Biology
- Pulmonology
Background:
- Alveolar macrophages (AMs) maintain lung health through efferocytosis and antimicrobial functions.
- Pattern recognition receptors (PRRs) like TLR-2, MR, and SRs aid in Streptococcus pneumoniae binding.
- The mechanism of impaired S. pneumoniae clearance after efferocytosis is unclear.
Purpose of the Study:
- To investigate if prostaglandin E2 (PGE2) produced during efferocytosis by AMs inhibits the clearance of non-opsonized S. pneumoniae.
- To elucidate the signaling pathway involved in this inhibition.
Main Methods:
- Resident AMs were treated with EP receptor antagonist, cyclooxygenase, and PKA inhibitors.
- Cells were incubated with apoptotic Jurkat T cells (efferocytosis) followed by challenge with S. pneumoniae.
- Bacterial phagocytosis and killing were assessed.
Main Results:
- Efferocytosis slightly reduced S. pneumoniae phagocytosis but significantly inhibited bacterial killing by AMs.
- This inhibition was dependent on PGE2 production, EP2-EP4/cAMP/PKA pathway activation, and reduced H2O2 production.
- PGE2 production during efferocytosis impairs AMs' ability to clear S. pneumoniae.
Conclusions:
- PGE2 produced by AMs during efferocytosis inhibits hydrogen peroxide (H2O2) production.
- This PGE2-mediated effect, via the EP2-EP4/cAMP/PKA pathway, impairs efficient clearance of non-opsonized S. pneumoniae.