BAFF and APRIL counterregulate susceptibility to inflammation-induced preterm birth
Jessica R. Doll,
Maria E. Moreno-Fernandez,
Traci E. Stankiewicz,
Jennifer L. Wayland,
Adrienne Wilburn,
Benjamin Weinhaus,
Claire A. Chougnet,
Daniela Giordano,
Monica Cappelletti,
Pietro Presicce,
Suhas G. Kallapur,
Nathan Salomonis,
Tamara Tilburgs,
Senad Divanovic
Affiliations
Jessica R. Doll
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Maria E. Moreno-Fernandez
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Traci E. Stankiewicz
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Jennifer L. Wayland
Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
Adrienne Wilburn
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
Benjamin Weinhaus
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
Claire A. Chougnet
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
Daniela Giordano
Department of Medicine, Division of Rheumatology, University of Washington, Seattle, WA 98195, USA
Monica Cappelletti
Division of Neonatology and Developmental Biology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Pietro Presicce
Division of Neonatology and Developmental Biology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Suhas G. Kallapur
Division of Neonatology and Developmental Biology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Nathan Salomonis
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Tamara Tilburgs
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Senad Divanovic
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Corresponding author
Summary: Clinical evidence points to a function for B cell-activating factor (BAFF) in pregnancy. However, direct roles for BAFF-axis members in pregnancy have not been examined. Here, via utility of genetically modified mice, we report that BAFF promotes inflammatory responsiveness and increases susceptibility to inflammation-induced preterm birth (PTB). In contrast, we show that the closely related A proliferation-inducing ligand (APRIL) decreases inflammatory responsiveness and susceptibility to PTB. Known BAFF-axis receptors serve a redundant function in signaling BAFF/APRIL presence in pregnancy. Treatment with anti-BAFF/APRIL monoclonal antibodies or BAFF/APRIL recombinant proteins is sufficient to manipulate susceptibility to PTB. Notably, macrophages at the maternal-fetal interface produce BAFF, while BAFF and APRIL presence divergently shape macrophage gene expression and inflammatory function. Overall, our findings demonstrate that BAFF and APRIL play divergent inflammatory roles in pregnancy and provide therapeutic targets for mitigating risk of inflammation-induced PTB.
