IL-1 signaling mediates intrauterine inflammation and chorio-decidua neutrophil recruitment and activation
Pietro Presicce, Chan-Wook Park, Paranthaman Senthamaraikannan, Sandip Bhattacharyya, Courtney Jackson, Fansheng Kong, Cesar M. Rueda, Emily DeFranco, Lisa A. Miller, David A. Hildeman, Nathan Salomonis, Claire A. Chougnet, Alan H. Jobe, Suhas G. Kallapur
Pietro Presicce, Chan-Wook Park, Paranthaman Senthamaraikannan, Sandip Bhattacharyya, Courtney Jackson, Fansheng Kong, Cesar M. Rueda, Emily DeFranco, Lisa A. Miller, David A. Hildeman, Nathan Salomonis, Claire A. Chougnet, Alan H. Jobe, Suhas G. Kallapur
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Research Article Immunology Reproductive biology

IL-1 signaling mediates intrauterine inflammation and chorio-decidua neutrophil recruitment and activation

Abstract

Neutrophil infiltration of the chorioamnion-decidua tissue at the maternal-fetal interface (chorioamnionitis) is a leading cause of prematurity, fetal inflammation, and perinatal mortality. We induced chorioamnionitis in preterm rhesus macaques by intraamniotic injection of LPS. Here, we show that, during chorioamnionitis, the amnion upregulated phospho-IRAK1–expressed neutrophil chemoattractants CXCL8 and CSF3 in an IL-1–dependent manner. IL-1R blockade decreased chorio-decidua neutrophil accumulation, neutrophil activation, and IL-6 and prostaglandin E2 concentrations in the amniotic fluid. Neutrophils accumulating in the chorio-decidua had increased survival mediated by BCL2A1, and IL-1R blockade also decreased BCL2A1+ chorio-decidua neutrophils. Readouts for inflammation in a cohort of women with preterm delivery and chorioamnionitis were similar to findings in the rhesus macaques. IL-1 is a potential therapeutic target for chorioamnionitis and associated morbidities.

Authors

Pietro Presicce, Chan-Wook Park, Paranthaman Senthamaraikannan, Sandip Bhattacharyya, Courtney Jackson, Fansheng Kong, Cesar M. Rueda, Emily DeFranco, Lisa A. Miller, David A. Hildeman, Nathan Salomonis, Claire A. Chougnet, Alan H. Jobe, Suhas G. Kallapur

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Figure 5

IA LPS induced expression of the prosurvival factor BCL2A1/BFL1 in neutrophils is IL-1 dependent.

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IA LPS induced expression of the prosurvival factor BCL2A1/BFL1 in neutr...
Expression of BCL2A1/BFL1 mRNA by quantitative PCR in the rhesus CAD (A) (Ctrl, n = 13; LPS, n = 11; LPS + rhIL-1ra, n = 6). Representative sections (n = 5) from rhesus chorioamnion-decidua paraffin-embedded blocks were stained with DAPI (blue) and BCL2A1/BFL1 (red). Controls (B), IA LPS (C), and LPS + IL-1ra (D). Magnified inset (60×) in C demonstrate cells with polymorphonuclear morphology expressing BCL2A1. (E) Cell count/high-powered field (HPF, 40×) of cells in the chorio-decidua interface showing fewer BCL2A1+ neutrophils in LPS + rhIL-1ra compared with LPS groups (Ctrl, n = 5; LPS, n = 5; LPS + rhIL-1ra, n = 5). (F) Increased expression of BCL2A1/BFL1 and BCLXL in flow-sorted chorio-decidua neutrophils from IA LPS–exposed animals (n = 3) compared with immunomagnetic bead purified blood neutrophils from the same animal (n = 4). (G) Chorio-decidua cell suspension were cultured for 16 hours (n = 5–14). ML214 (inhibitor of BCL2A1) treatment (5 μM) decreased frequency of chorio-decidua annexin V–/7aad– (nonapoptotic) neutrophils by flow cytometry, while ABT-737 (inhibitor of BCL2 but not BCL2A1; 0.1 μM) did not show any significant effect. am, amnion; ch, chorion; dp, decidua parietalis. Data are mean ± SEM, *P < 0.05 between comparators by Mann-Whitney test.