Immune status of decidual macrophages is dependent on the CCL2/CCR2/JAK2 pathway during early pregnancy

• Published in: American journal of reproductive immunology (1989) 2021-11, Vol.86 (5), p.e13480-n/a
• Main Authors: Wei, Chun‐Yan, Li, Ming‐Qing, Zhu, Xiao‐Yong, Li, Da‐Jin
• Format: Article
• Language: English
• Subjects: Adult; Animals; Autocrine signalling; CC chemokine receptors; CCL2; CCR2; CCR2 protein; CD36 antigen; CD86 antigen; Cell culture; Cells, Cultured; Chemokine CCL2 - metabolism; Chemokine receptors; Coculture Techniques; Decidua; Decidua - drug effects; Decidua - enzymology; Decidua - immunology; decidual macrophages; Embryo Loss - enzymology; Embryo Loss - immunology; Enzyme inhibitors; Female; Fetal resorption; Fetuses; Flow cytometry; Histocompatibility, Maternal-Fetal; Homeostasis; Humans; Immune status; Immune Tolerance; Immunological tolerance; JAK2; Janus kinase; Janus kinase 2; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; Janus Kinase Inhibitors - pharmacology; Macrophages; Macrophages - drug effects; Macrophages - enzymology; Macrophages - immunology; Mice; Mice, Inbred C57BL; Monocyte chemoattractant protein 1; Monocytes; Paracrine signalling; Phenotype; Polymerase chain reaction; Pregnancy; Pregnancy Outcome; Receptors, CCR2 - antagonists & inhibitors; Receptors, CCR2 - metabolism; Signal Transduction; Stat3 protein; Stromal cells; Stromal Cells - drug effects; Stromal Cells - enzymology; Stromal Cells - immunology; Transcription; Trophoblasts; Young Adult
• ISSN: 1046-7408; 1600-0897
• DOI: 10.1111/aji.13480

Problem Decidual macrophages (dMφ) play an important role in the formation of maternal–fetal immune tolerance. However, factors that influence the immune status of dMφ and the related potential mechanisms have not been elucidated to date. Method of study The gene transcription in dMφ, decidual stromal cells (DSCs), extravillous trophoblasts (EVTs), and peripheral monocytes (pMo) from human samples were measured using real‐time polymerase chain reaction (PCR). Monocyte‐DSC co‐culture was established to explore whether DSCs influenced dMφ polarization via C‐C motif ligand 2 (CCL2)‐C‐C chemokine receptor (CCR2) binding using flow cytometry. In vivo, changes in dMφ percentage and M1 and M2 marker expression after treatment with CCR2 or Janus kinase 2 (JAK2) inhibitor were detected with flow cytometry. Embryo resorption percentages in the above groups were also analyzed. Results We found that dMφ were an M1/M2 mixed status at the maternal–fetal interface during early pregnancy. CCL2 influenced the immune status of dMφ in an autocrine and paracrine manner. As a downstream regulator of CCR2 and triggers the Stat3 pathway, JAK2 was found to be essential for dMφ homeostasis in vivo. JAK2 inhibitor decreased the dMφ proportion and attenuated Ki67, CD36, CD86, CD206, TNF, and IL‐10 expression in dMφ at E8.5 d. Moreover, CCR2‐JAK2 pathway inhibition decreased the width of the placental labyrinth layer, further influencing the pregnancy outcome. Conclusion The M1/M2 mixed immune status of dMφ was regulated by DSCs via CCR2, and the CCL2/CCR2/JAK2 pathway was essential for the immune status of dMφ and the outcome of early pregnancy.