sEH promotes macrophage phagocytosis and lung clearance of Streptococcus pneumoniae
Hong Li, … , Shepherd H. Schurman, Darryl C. Zeldin
Hong Li, … , Shepherd H. Schurman, Darryl C. Zeldin
Published September 30, 2021
Citation Information: J Clin Invest. 2021;131(22):e129679. https://doi.org/10.1172/JCI129679.
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Research Article Cell biology Infectious disease

sEH promotes macrophage phagocytosis and lung clearance of Streptococcus pneumoniae

Abstract

Epoxyeicosatrienoic acids (EETs) have potent antiinflammatory properties. Hydrolysis of EETs by soluble epoxide hydrolase/ epoxide hydrolase 2 (sEH/EPHX2) to less active diols attenuates their antiinflammatory effects. Macrophage activation is critical to many inflammatory responses; however, the role of EETs and sEH in regulating macrophage function remains unknown. Lung bacterial clearance of Streptococcus pneumoniae was impaired in Ephx2-deficient (Ephx2–/–) mice and in mice treated with an sEH inhibitor. The EET receptor antagonist EEZE restored lung clearance of S. pneumoniae in Ephx2–/– mice. Ephx2–/– mice had normal lung Il1b, Il6, and Tnfa expression levels and macrophage recruitment to the lungs during S. pneumoniae infection; however, Ephx2 disruption attenuated proinflammatory cytokine induction, Tlr2 and Pgylrp1 receptor upregulation, and Ras-related C3 botulinum toxin substrates 1 and 2 (Rac1/2) and cell division control protein 42 homolog (Cdc42) activation in PGN-stimulated macrophages. Consistent with these observations, Ephx2–/– macrophages displayed reduced phagocytosis of S. pneumoniae in vivo and in vitro. Heterologous overexpression of TLR2 and peptidoglycan recognition protein 1 (PGLYRP1) in Ephx2–/– macrophages restored macrophage activation and phagocytosis. Human macrophage function was similarly regulated by EETs. Together, these results demonstrate that EETs reduced macrophage activation and phagocytosis of S. pneumoniae through the downregulation of TLR2 and PGLYRP1 expression. Defining the role of EETs and sEH in macrophage function may lead to the development of new therapeutic approaches for bacterial diseases.

Authors

Hong Li, J. Alyce Bradbury, Matthew L. Edin, Joan P. Graves, Artiom Gruzdev, Jennifer Cheng, Samantha L. Hoopes, Laura M. DeGraff, Michael B. Fessler, Stavros Garantziotis, Shepherd H. Schurman, Darryl C. Zeldin

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Figure 10

Proposed model for the regulation of bacterial clearance by EETs.

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Proposed model for the regulation of bacterial clearance by EETs. In WT ...
In WT mice, PAMPs from S. pneumoniae (PGN) are recognized by PRRs (TLR2 and PGLYRP1), and this leads to upregulation of sEH, resulting in reduced EET levels. Low EETs permit enhanced signaling through ERK, p38 MAPK, and NF-κB and lead to the production of proinflammatory cytokines (IL-1, IL-6, TNF-α) and increased expression of PRRs. A positive feedback loop further enhances downstream signaling and ultimately leads to efficient activation of Rho family GTPases (Rac1 and Cdc42), which are responsible for enhanced bacterial phagocytosis and clearance. In Ephx2–/– mice, PAMPs cannot upregulate sEH, and this results in reduced EET hydrolysis and increased EET levels. Increased EETs attenuate downstream signaling through ERK, p38 MAPK, and NF-κB, reduce proinflammatory cytokine production, reduce the expression of PRRs, and diminish activation of the Rho family GTPases, resulting in impaired bacterial phagocytosis and clearance.