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This Article Full Text (PDF) All Versions of this Article: jimmunol.0900788v1 183/2/1144    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Thaxton, J. E. Articles by Sharma, S. PubMed PubMed Citation Articles by Thaxton, J. E. Articles by Sharma, S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information High Risk Pregnancy

TLR9 Activation Coupled to IL-10 Deficiency Induces Adverse Pregnancy Outcomes¹

Jessica E. Thaxton^*, Roberto Romero and Surendra Sharma^2,*

*Department of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI 02905; and Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health/Department of Health and Human Services, Detroit, MI 48201

Pregnancy outcome is severely compromised by intrauterine infections and inflammation. Although the pregnant uterine microenvironment is replete with innate immune cells and TLR expression, the mechanisms that facilitate adverse effects of their activation are largely unknown. In this study, we mimic the activation of TLR9 with its pathogenic ligand hypomethylated CpG and demonstrate that IL-10 proficiency protects against CpG-induced pregnancy complications. We show that fetal resorption and preterm birth are rapidly induced in IL-10^–/– mice by low doses of CpG (25 µg/mouse) when injected i.p. on gestational day 6 or gestational day 14, respectively. In contrast, wild-type mice failed to experience such effects at comparable doses, but pups born at term displayed craniofacial/limb defects in response to higher doses (400 µg/mouse). Pregnancy complications in IL-10^–/– mice were associated with unexpected and robust TLR9-triggered activation and amplification of uterine neutrophil and macrophage subpopulations followed by their migration to the placental zone. Furthermore, a dramatic increase in serum levels of mouse KC and TNF- production by uterine F4/80⁺ cells, but not uterine NK or Gr-1⁺CD11b⁺ cells, was observed. Depletion of F4/80⁺ macrophages or neutralization of TNF- rescued pregnancy to term. Our results have important implications for IL-10-mediated "uterine tolerance" against CpG-driven innate immune activation.

²Address correspondence and reprint requests to Dr. Surendra Sharma, Department of Pediatrics, Women and Infants Hospital, 101 Dudley Street, Providence, RI 02905. E-mail address: ssharma{at}wihri.org

¹ This work was supported in part by a grant from National Institutes of Health, National Center for Research Resources (P20RR018728), The Intramural Division of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and Subcontract WSU05056 under National Institute of Child Health and Human Development Contract N01-HD-2-3342. J.E.T. was supported by a Superfund Basic Research Program Award (P42ES013660) from the National Institute of Environmental Health Sciences.