Receptor‐interacting protein kinase 2 contributes to host innate immune responses against Fusobacterium nucleatum in macrophages and decidual stromal cells

Problem Chorioamnionitis is caused by a bacterial infection that ascends from the vagina and can cause adverse pregnancy outcomes (APOs). Fusobacterium nucleatum (F. nucleatum) is a periodontal pathogen associated with the occurrence of APOs. In this study, we evaluated whether receptor‐interacting protein kinase 2 (Ripk2), an adaptor protein of the cytosolic receptors nucleotide‐binding oligomerization domain (NOD)1 and NOD2, in macrophages and human decidual stromal cells (hDSCs) contributes to immune responses against F. nucleatum. Method of Study Bone marrow‐derived macrophages (BMDMs) isolated from wild‐type (WT) and Ripk2‐deficient mice and hDSCs were cultured with F. nucleatum (MOI 1, 10, 100). BMDMs and hDSCs were assessed using enzyme‐linked immunosorbent assay, Western blot analysis, real‐time PCR, and nitrite assay. Results Fusobacterium nucleatum‐induced production of IL‐6, but not of TNF‐α and IL‐10, was lower in Ripk2‐deficient BMDMs than in WT cells. Western blotting revealed a decrease in F. nucleatum‐induced p65 phosphorylation in Ripk2‐deficient macrophages, whereas mitogen‐activated protein kinases activation was comparable between WT and Ripk2‐deficient cells. The production of nitric oxide (NO) in response to F. nucleatum and the gene and protein expression of inducible NO synthase was impaired in Ripk2‐deficient BMDMs. In hDSCs, F. nucleatum upregulated the gene and protein expression of NOD1, NOD2, and Ripk2 in a time‐dependent manner. F. nucleatum also increased the production of IL‐6, CXCL8, and CCL2, whereas this production was decreased by the Ripk2 inhibitors SB203580 and PP2. Conclusions In conclusion, Ripk2 signaling appears to contribute to the F. nucleatum‐induced immune response and can be a preventive and therapeutic target against APOs.