BAFF and APRIL counterregulate susceptibility to inflammation-induced preterm birth

• Published in: Cell reports (Cambridge) Vol. 42; no. 4; p. 112352
• Main Authors: Doll, Jessica R., Moreno-Fernandez, Maria E., Stankiewicz, Traci E., Wayland, Jennifer L., Wilburn, Adrienne, Weinhaus, Benjamin, Chougnet, Claire A., Giordano, Daniela, Cappelletti, Monica, Presicce, Pietro, Kallapur, Suhas G., Salomonis, Nathan, Tilburgs, Tamara, Divanovic, Senad
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.04.2023; Elsevier
• Subjects: Animals; B-Cell Activating Factor; BLys; CP: Immunology; cytokine signaling; Female; Inflammation; labor; macrophage; Mice; parturition; Pregnancy; Premature Birth; Signal Transduction; therapeutic; TNF superfamily; Tumor Necrosis Factor Ligand Superfamily Member 13 - genetics; therapeutic; CP: Immunology; TNF superfamily; pregnancy; cytokine signaling; macrophage; BLys; parturition; labor
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112352

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. [Display omitted] •BAFF promotes susceptibility to preterm birth•APRIL reduces susceptibility to preterm birth•Targeting BAFF/APRIL axis has potential for therapeutic utility in preterm birth•BAFF and APRIL modulate macrophage gene expression and inflammatory vigor Doll et al. demonstrate that B cell-activating factor (BAFF) promotes inflammatory responsiveness and susceptibility to preterm birth while the closely related a proliferation-inducing ligand (APRIL) mediates the opposite effect. Notably, BAFF and APRIL play divergent roles in pregnancy and could be therapeutically targeted for mitigating risk of inflammation-induced preterm birth.