title: Platelets impair natural killer cell reactivity and function in endometriosis through multiple mechanisms.
abstract: Do platelets have any role in the reduced cytotoxicity of natural killer (NK) cells in endometriosis?
  
  
  
  Platelets impair NK cell reactivity and function in endometriosis through multiple mechanisms.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Not applicable.
  
  
  
  This study is confined by the limitation of animal and in vitro experimentation and the lack of direct human data.
  
  
  
  Anti-platelet treatment holds promise in treating endometriosis.
  
  
  
  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.
authors.affiliation: Shanghai Obstetrics and Gynecology Hospital, Fudan University Shanghai College of Medicine, Shanghai, China.
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Du
authors.affiliation: Shanghai Obstetrics and Gynecology Hospital, Fudan University Shanghai College of Medicine, Shanghai, China.
authors.forename: Xishi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Obstetrics and Gynecology Hospital, Fudan University Shanghai College of Medicine, Shanghai, China.
authors.forename: Sun-Wei
authors.initials: SW
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis; D001792:Blood Platelets / Q000502:physiology*; D002460:Cell Line; D018920:Coculture Techniques; D004715:Endometriosis / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053773:Transforming Growth Factor beta1
keywords: IFN-γ; MHC class I; NK cells; NKG2D; TGF-β1; cytotoxicity; endometriosis; platelet