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 5

Type I IFN signaling in hematopoietic cells is sufficient for secondary inflammatory challenge–driven cytokine production in mice.

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Type I IFN signaling in hematopoietic cells is sufficient for secondary ...
(A) Left: A schematic overview of experimental model employed to define the type I IFN receptor–responsive (IFNAR-responsive) cell types sufficient to prime for secondary inflammatory challenge–driven proinflammatory cytokine production. Right: Bone marrow from WT and IFNAR–/– (IKO) mice (n = 3–4/condition) was reciprocally transferred into WT and IFNAR–/– recipients and mice were mock treated (saline) or treated with recombinant mouse IFN-β (104 U/mouse; 4 hours) prior to being challenged with LPSlow (25 μg/mouse; 4 hours) and serum IL-6 and TNF levels were quantified by in vivo cytokine capture assay (IVCCA). (B) Left: Representative flow cytometry histogram showing modulation of IL-6 and TNF expression after each stimulation. Murine peripheral blood mononuclear cells (n = 3) were mock treated or treated with mouse IFN-β (250 U/ml; 4 hours) prior to being stimulated with LPS (100 ng/ml; 4 hours), and IL-6 and TNF levels were quantified (right) by intracellular flow cytometry. MFI, mean fluorescence intensity; NS, saline. (C) WT mice (n = 3–4/condition) were challenged with recombinant mouse IFN-β (104 U/mouse), LPSlow, or IFN-β + LPS and vice versa, and serum IL-6 and TNF levels were quantified by IVCCA. (D) WT and IFNAR–/– murine peritoneal macrophages (n = 3/genotype), were treated as in B and IL-6 levels were quantified by ELISA. (A, C, and D) Dashed red line represents 100% induction of cytokine following LPSlow-alone challenge in WT mice. Data represent percentage change over LPSlow (WT) ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by ANOVA followed by Tukey’s correction.