Type I interferons regulate susceptibility to inflammation-induced preterm birth
Monica Cappelletti, Pietro Presicce, Matthew J. Lawson, Vandana Chaturvedi, Traci E. Stankiewicz, Simone Vanoni, Isaac T.W. Harley, Jaclyn W. McAlees, Daniel A. Giles, Maria E. Moreno-Fernandez, Cesar M. Rueda, Paranth Senthamaraikannan, Xiaofei Sun, Rebekah Karns, Kasper Hoebe, Edith M. Janssen, Christopher L. Karp, David A. Hildeman, Simon P. Hogan, Suhas G. Kallapur, Claire A. Chougnet, Sing Sing Way, Senad Divanovic
Monica Cappelletti, Pietro Presicce, Matthew J. Lawson, Vandana Chaturvedi, Traci E. Stankiewicz, Simone Vanoni, Isaac T.W. Harley, Jaclyn W. McAlees, Daniel A. Giles, Maria E. Moreno-Fernandez, Cesar M. Rueda, Paranth Senthamaraikannan, Xiaofei Sun, Rebekah Karns, Kasper Hoebe, Edith M. Janssen, Christopher L. Karp, David A. Hildeman, Simon P. Hogan, Suhas G. Kallapur, Claire A. Chougnet, Sing Sing Way, Senad Divanovic
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Research Article Immunology Inflammation

Type I interferons regulate susceptibility to inflammation-induced preterm birth

Abstract

Preterm birth (PTB) is a leading worldwide cause of morbidity and mortality in infants. Maternal inflammation induced by microbial infection is a critical predisposing factor for PTB. However, biological processes associated with competency of pathogens, including viruses, to induce PTB or sensitize for secondary bacterial infection–driven PTB are unknown. We show that pathogen/pathogen-associated molecular pattern–driven activation of type I IFN/IFN receptor (IFNAR) was sufficient to prime for systemic and uterine proinflammatory chemokine and cytokine production and induction of PTB. Similarly, treatment with recombinant type I IFNs recapitulated such effects by exacerbating proinflammatory cytokine production and reducing the dose of secondary inflammatory challenge required for induction of PTB. Inflammatory challenge–driven induction of PTB was eliminated by defects in type I IFN, TLR, or IL-6 responsiveness, whereas the sequence of type I IFN sensing by IFNAR on hematopoietic cells was essential for regulation of proinflammatory cytokine production. Importantly, we also show that type I IFN priming effects are conserved from mice to nonhuman primates and humans, and expression of both type I IFNs and proinflammatory cytokines is upregulated in human PTB. Thus, activation of the type I IFN/IFNAR axis in pregnancy primes for inflammation-driven PTB and provides an actionable biomarker and therapeutic target for mitigating PTB risk.

Authors

Monica Cappelletti, Pietro Presicce, Matthew J. Lawson, Vandana Chaturvedi, Traci E. Stankiewicz, Simone Vanoni, Isaac T.W. Harley, Jaclyn W. McAlees, Daniel A. Giles, Maria E. Moreno-Fernandez, Cesar M. Rueda, Paranth Senthamaraikannan, Xiaofei Sun, Rebekah Karns, Kasper Hoebe, Edith M. Janssen, Christopher L. Karp, David A. Hildeman, Simon P. Hogan, Suhas G. Kallapur, Claire A. Chougnet, Sing Sing Way, Senad Divanovic

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Figure 6

IFN-β priming exacerbates secondary inflammatory challenge–driven cytokine production and correlates with preterm birth (PTB) in humans.

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IFN-β priming exacerbates secondary inflammatory challenge–driven cytoki...
(A) Peripheral blood mononuclear cells (PBMCs; n = 5) and decidual cells (n = 9) obtained from pregnant rhesus macaques were mock treated (saline) or treated with human IFN-β (250 U/ml; 6 hours) prior to being stimulated with LPS (100 ng/ml; 18 hours), and IL-6 and TNF levels were quantified by ELISA. (B) PBMCs (n = 5) and monocytes (n = 4) obtained from healthy human volunteers and decidual cells (n = 4) obtained from healthy pregnant human volunteers (n = 4) were treated with human IFN-β (250 U/ml; 6 hours) prior to being stimulated with LPS (100 ng/ml; 18 hours), and IL-6 and TNF levels were quantified by ELISA. (C) IFN-β, IL-6, and TNF mRNA expression in the maternal/fetal membranes (chorion-amnion-decidua) from pregnant human volunteers with chorioamnionitis (Term: n = 6; PTB: n = 8). (A and B) Data represent percentage change over LPS ± SEM. Significance determined by ANOVA followed by Tukey’s correction. (C) Data represent fold change over the average value for chorioamnionitis-negative samples after normalization to the housekeeping 18S RNA. *P < 0.05, **P < 0.01 by Mann-Whitney test.