IFN-γ induces aberrant CD49b⁺ NK cell recruitment through regulating CX3CL1: a novel mechanism by which IFN-γ provokes pregnancy failure.
Interferon-γ (IFN-γ), a pleiotropic lymphokine, has important regulatory effects on many cell types. Although IFN-γ is essential for the initiation of uterine vascular modifications and maintenance of decidual integrity, IFN-γ administration can also cause pregnancy failure in many species. However, little is known about the effector mechanisms involved. In this study, using an IFN-γ-induced abortion mouse model, we reported that no Dolichos biflorus agglutinin lectin-positive uterine natural killer (uNK) cells were observed in the uteri from IFN-γ-induced abortion mice. By contrast, the percentage of CD3(-)CD49b(+) NK cells in the uterus and blood from a foetal resorption group was significantly higher than that of the control group. Similarly, significantly upregulated expression of CD49b (a pan-NK cell marker), CX3CL1 and CX3CR1 (CX3CL1 receptor) was detected in the uteri of IFN-γ-induced abortion mice. Using isolated uterine stromal cells, we showed that upregulated expression of CX3CL1 by IFN-γ was dependent on a Janus family kinase 2-signal transducers and activators of transcription 1 (JAK2-STAT1) pathway. We further demonstrated the chemotactic activity of CX3CL1 in uterine stromal cell conditioned medium on primary splenic NK cells. Finally, we observed increased recruitment of CD49b(+) NK cells into the endometrium after exogenous CX3CL1 administration. Collectively, our findings indicate that IFN-γ can significantly increase uterine CX3CL1 expression via activation of the JAK2-STAT1 pathway, thus inducing CD49b(+) NK cell uterine homing, and eventually provoke foetal loss. Thus, we provide a new line of evidence correlating the deleterious effects of IFN-γ on pregnancy with the aberrant regulation of CX3CL1 and CD49b(+) NK cells.
1] State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China.
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ZY
Li
1] State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China.
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Chao
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.
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HY
Liu
1] State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China.
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ZH
Song
1] State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China.
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Li
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.
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Zhang
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.
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Yang
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.
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JP
Peng
D000028:Abortion, Induced; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D005260:Female; D005333:Fetus; D005786:Gene Expression Regulation; D039421:Integrin alpha2 / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011247:Pregnancy; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014599:Uterus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; C027654:Dolichos biflorus lectin receptor; D039421:Integrin alpha2; D019707:Receptors, Chemokine; D011975:Receptors, Mitogen; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2