Type I interferons regulate susceptibility to inflammation-induced preterm birth
Monica Cappelletti, … , Sing Sing Way, Senad Divanovic
Monica Cappelletti, … , Sing Sing Way, Senad Divanovic
Published March 9, 2017
Citation Information: JCI Insight. 2017;2(5):e91288. https://doi.org/10.1172/jci.insight.91288.
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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 1

Viral infection primes for secondary inflammatory challenge–driven cytokine production and induction of preterm birth (PTB) in mice.

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Viral infection primes for secondary inflammatory challenge–driven cytok...
(A) A schematic overview of the tractable double-hit preclinical model of PTB induction employed to define the ability of viral infections to prime for secondary inflammatory challenge–driven PTB. Gravid WT mice were mock infected (saline) or infected with very low dose influenza virus (PR8; 6 × 102 PFU/mouse) or very low dose lymphocytic choriomeningitis virus (LCMV; 5 × 104 PFU/mouse) on day 14 of gestation prior to being mock challenged (saline) or challenged with LPS (25 μg/mouse = low; 75 μg/mouse = high) on day 16 of gestation, and the incidence of PTB was quantified. (B) WT mice (n = 3–6/condition) were mock infected or infected as described above in A with influenza virus or LCMV for 48 hours prior to being mock challenged or challenged with LPSlow for 4 hours, and serum IFN-β, IL-6, and TNF levels were quantified by type I IFN activity assay and in vivo cytokine capture assay (IVCCA), respectively. (C) A schematic overview of the tractable double-hit preclinical model of PTB induction employed to define the ability of viral mimetic to prime for secondary inflammatory challenge–driven PTB. Gravid WT mice were challenged with poly(I:C) alone (100 μg/mouse = low; 250 μg/mouse = high), or primed with poly(I:C) for 4 hours prior to being challenged with LPSlow on day 16 of gestation and the incidence of PTB was quantified. (D) WT mice (n = 3–6/condition) were challenged as described above in C with poly(I:C) alone or primed with poly(I:C) prior to being challenged with LPSlow for 4 hours and serum IFN-β, IL-6, and TNF levels were quantified by type I IFN activity assay and IVCCA, respectively. (A and C) Data represent percentage induction of PTB. Term birth is defined as parturition on days 19–21 (all pups born alive). PTB is defined as parturition within 24 hours after TLR ligand challenge (all pups deceased). (B and D) Dashed red line represents 100% induction of cytokine following LPSlow-alone challenge in WT mice. Data (PR8, LCMV, LPSlow, PR8 + LPSlow, and LCMV + LPSlow) represent percentage change over LPSlow (WT) ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by ANOVA followed by Tukey’s correction.