Platelets impair natural killer cell reactivity and function in endometriosis through multiple mechanisms

Yanbo Du, Du Y, Liu X, Xishi Liu, Sun-Wei Guo, Guo SW, Sun‐Wei Guo
Human Reproduction · 2017 · vol. 32(4) , pp. 794–810 · doi:10.1093/humrep/dex014 · PMID:28184445 · W2587258981
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Platelets impair natural killer cell function in endometriosis by coating target cells and reducing NK cell degranulation and activating receptor expression, partly via TGF-β1 signaling.

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Abstract

Study question: Do platelets have any role in the reduced cytotoxicity of natural killer (NK) cells in endometriosis? Summary answer: Platelets impair NK cell reactivity and function in endometriosis through multiple mechanisms. What is known already: Platelets play an important role in the development of endometriosis, and platelet-derived transforming growth factor-β1 (TGF-β1) suppresses the expression of NK Group 2, Member D (NKG2D) on NK cells, resulting in reduced cytotoxicity in women with endometriosis. Study design size, duration: Experiments on mice with induced endometriosis in which either platelets, NK cells or both were depleted and controls (none depleted). In vitro experiments with NK cells, platelets and, as target cells, endometriotic epithelial cell and endometrial stromal cell lines. Participants/materials setting methods: Immunohistochemistry analysis of ectopic endometrial tissues from mice with induced endometriosis receiving either platelet depletion (PD), NK cell depletion, or both or none. Immunofluorescence, flow cytometry and gene expression analysis for major histocompatibility complex class I (MHC-I) expression in target cells. Cytotoxicity and degranulation assays and the measurement of interferon (IFN)-γ secretion for the evaluation of NK cytotoxicity. Flow cytometry and gene expression for the expression of NK cell receptors. Main results and the role of chance: PD resulted in significantly reduced lesion weight in mice with induced endometriosis, but NK cell depletion as well as concomitant platelet and NK cell depletion increased the weight, suggesting that the anti-endometriosis effect of PD is mediated, at least in part, by increased NK cell cytotoxicity against endometriotic cells. Co-incubation of target cells with platelets resulted in rapid platelet coating as well as increased MHC-I expression in these cells, effectively providing a cloak of 'pseudo-self' to these cells to shield against NK cell lysis. It also reduced the expression of NKG2D ligands MICA and MICB and reduced the NK cell cytotoxicity. In addition, co-incubation of NK cells with platelets impaired the NK cell cytotoxicity as well. This impaired NK cell cytotoxicity was not due to the increased NK cell apoptosis, but, rather, through reduced NK cell degranulation and IFN-γ production, and reduced expression of activating receptors NKG2D and NKp46 and increased expression of inhibitory receptor KIR2DL1 in NK cells. Inhibition of TGF-β1 signaling partially restored the aberrant expression of NKG2D, NKp46 and KIR2DL1, and partially restored the impaired NK cell cytotoxicity induced by activated platelets and their releasate. Large scale data: Not applicable. Limitations reasons for caution: This study is confined by the limitation of animal and in vitro experimentation and the lack of direct human data. Wider implications of the findings: Anti-platelet treatment holds promise in treating endometriosis. Study funding/competing interests: The National Natural Science Foundation of China (81471434 to S.W.G., 81270676 to S.W.G., 81370695 to X.S.L. and 81671436 to X.S.L). None of the authors has anything to disclose.

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Condition tags

endometriosis

MeSH descriptors

Blood Platelets Endometriosis Killer Cells, Natural Animals Apoptosis Blood Platelets Cell Line Coculture Techniques Endometriosis Epithelial Cells Epithelial Cells Epithelial Cells Epithelial Cells Female Flow Cytometry Gene Expression Profiling Humans Killer Cells, Natural Mice Mice, Inbred BALB C

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