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 3

Necessity of IFNAR signaling in priming of secondary inflammatory challenge–driven cytokine production and induction of preterm birth (PTB) in mice is conserved across pathogen class.

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Necessity of IFNAR signaling in priming of secondary inflammatory challe...
(A) A schematic overview of the tractable double-hit preclinical model of PTB induction employed to define the ability of Listeria infection to prime for LPS-driven PTB. Gravid WT mice were mock infected (saline) or infected with L. monocytogenes (Lm) (WT, 1 × 102 CFU; LmΔ [ΔLLOΔPLC], 1 × 108 CFU) on day 15 of gestation prior to being mock challenged (saline) or challenged with LPSlow (25 μg/mouse) on day 16 of gestation, and the incidence of PTB was quantified. (B) WT mice (n = 3–5/condition) were mock infected or infected with Lm (WT and LmΔ) for 24 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 and E) Gravid type I IFN receptor–deficient (IFNAR–/–) and IL-6–/– mice were treated as in A and the incidence of PTB was quantified. (D and F) IFNAR–/– and IL-6–/– mice (n = 3–4/condition) were treated as in B and serum IFN-β, IL-6, and TNF levels were quantified. (A, C, and E) Data represent percentage induction of term birth or PTB. (B, D, and F) Dashed red line represents 100% induction of cytokine following LPSlow-alone challenge in WT mice. Data represent percentage change over LPSlow (WT) ± SEM. ***P < 0.001 by ANOVA followed by Tukey’s correction.