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
View: Text | PDF
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

×

Figure 4

IFN-β is sufficient to prime for secondary inflammatory challenge–driven cytokine production and induction of preterm birth (PTB) in mice.

Options: View larger image (or click on image) Download as PowerPoint
IFN-β is sufficient to prime for secondary inflammatory challenge–driven...
(A) A schematic overview of the tractable double-hit preclinical model of PTB induction employed to define the sufficiency of IFN-β to prime for secondary inflammatory challenge–driven PTB. Gravid WT mice were treated with IL-6–neutralizing Ab or isotype control Ab (500 μg/mouse) and challenged with recombinant mouse IFN-β (104 U/mouse) or LPS alone, or primed with IFN-β (4 hours) prior to being 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 challenged with recombinant mouse IFN-β (104 U/mouse) or LPS alone, or primed with IFN-β (4 hours) prior to being challenged with LPS (4 hours), and serum IFN-β, IL-6, and TNF levels were quantified by in vivo cytokine capture assay. (C and D) Gravid WT (n = 3/condition) mice were challenged with LPS alone or primed with IFN-β (4 hours) prior to being challenged with LPS for 12 hours, and uterine CD68, CCL2, CCL4, IL-6, Cox-2, and TNF mRNA expression was quantified. (A) Data represent percentage induction of term birth or PTB. (B) Dashed red line represents 100% induction of cytokine following LPSlow-alone challenge in WT mice. Data represent percent change over LPSlow (WT) ± SEM. (C and D) Data represent fold change over nonstimulated condition. (B–D) *P < 0.05, **P < 0.01, ***P < 0.001 by ANOVA followed by Tukey’s correction.