Jessica A Sutton1,2, Lisa M Rogers2, Beverly R E A Dixon2, Leslie Kirk2, Ryan Doster2, Holly M Algood2,3,4, Jennifer A Gaddy2,3,4, Rebecca Flaherty5, Shannon D Manning5, David M Aronoff1,2,3,6. 1. Department of Microbiology and Immunology, Meharry Medical College School of Medicine, Nashville, Tennessee. 2. Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. 3. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. 4. Department of Veterans Affairs, Tennessee Valley Healthcare Systems, Nashville, Tennessee. 5. Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan. 6. Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee.
Abstract
PROBLEM: During pregnancy, Group B Streptococcus (GBS) can infect fetal membranes to cause chorioamnionitis, resulting in adverse pregnancy outcomes. Macrophages are the primary resident phagocyte in extraplacental membranes. Protein kinase D (PKD) was recently implicated in mediating pro-inflammatory macrophage responses to GBS outside of the reproductive system. This work aimed to characterize the human placental macrophage inflammatory response to GBS and address the extent to which PKD mediates such effects. METHOD: Primary human placental macrophages were infected with GBS in the presence or absence of a specific, small molecule PKD inhibitor, CRT 0066101. Macrophage phenotypes were characterized by evaluating gene expression, cytokine release, assembly of the NLRP3 inflammasome, and NFκB activation. RESULTS: GBS evoked a strong inflammatory phenotype characterized by the release of inflammatory cytokines (TNFα, IL-1β, IL-6 (P ≤ 0.05), NLRP3 inflammasome assembly (P ≤ 0.0005), and NFκB activation (P ≤ 0.05). Pharmacological inhibition of PKD suppressed these responses, newly implicating a role for PKD in mediating immune responses of primary human placental macrophages to GBS. CONCLUSION: PKD plays a critical role in mediating placental macrophage inflammatory activation in response to GBS infection.
PROBLEM: During pregnancy, Group B Streptococcus (GBS) can infect fetal membranes to cause chorioamnionitis, resulting in adverse pregnancy outcomes. Macrophages are the primary resident phagocyte in extraplacental membranes. Protein kinase D (PKD) was recently implicated in mediating pro-inflammatory macrophage responses to GBS outside of the reproductive system. This work aimed to characterize the human placental macrophage inflammatory response to GBS and address the extent to which PKD mediates such effects. METHOD: Primary human placental macrophages were infected with GBS in the presence or absence of a specific, small molecule PKD inhibitor, CRT 0066101. Macrophage phenotypes were characterized by evaluating gene expression, cytokine release, assembly of the NLRP3 inflammasome, and NFκB activation. RESULTS: GBS evoked a strong inflammatory phenotype characterized by the release of inflammatory cytokines (TNFα, IL-1β, IL-6 (P ≤ 0.05), NLRP3 inflammasome assembly (P ≤ 0.0005), and NFκB activation (P ≤ 0.05). Pharmacological inhibition of PKD suppressed these responses, newly implicating a role for PKD in mediating immune responses of primary human placental macrophages to GBS. CONCLUSION: PKD plays a critical role in mediating placental macrophage inflammatory activation in response to GBS infection.
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