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Background  Unexplained recurrent spontaneous abortion (URSA) is a common pregnancy complication and the etiology is unknown. URSA-associated lncRNAs are expected to be potential biomarkers for diagnosis, and might be related to the disease pathogenesis.    Objective  To investigate differential lncRNAs in peripheral blood of non-pregnant URSA patients and matched healthy control women and to explore the possible mechanism of differential lncRNAs leading to URSA.    Methods  We profiled lncRNAs expression in peripheral blood from 5 non-pregnant URSA patients and 5 matched healthy control women by lncRNA microarray analysis. Functions of URSA-associated lncRNAs were further investigated  in vitro .    Results  RP11-115N4.1 was identified as the most differentially expressed lncRNA which was highly upregulated in peripheral blood of non-pregnant URSA patients ( P  = 3.63E-07, Fold change = 2.96), and this dysregulation was further validated in approximately 26.67% additional patients (4/15). RP11-115N4.1 expression was detected in both lymphocytes and monocytes of human peripheral blood, and  in vitro  overexpression of RP11-115N4.1 decreased cell proliferation in K562 cells significantly. Furthermore, heat-shock HSP70 genes ( HSPA1A  and  HSPA1B ) were found to be significantly upregulated upon RP11-115N4.1 overexpression by transcriptome analysis ( HSPA1A  ( P  = 4.39E-08, Fold change = 4.17),  HSPA1B  ( P  = 2.26E-06, Fold change = 2.99)). RNA pull down and RNA immunoprecipitation assay (RIP) analysis demonstrated that RP11-115N4.1 bound to HNRNPH3 protein directly, which in turn activate heat-shock proteins (HSP70) analyzed by protein-protein interaction and  HNRNPH3  knockdown assays. Most importantly, the high expression of HSP70 was also verified in the serum of URSA patients and the supernatant of K562 cells with RP11-115N4.1 activation, and HSP70 in supernatant can exacerbate inflammatory responses in monocytes by inducing IL-6, IL-1β, and TNF-α and inhibit the migration of trophoblast cells, which might associate with URSA.    Conclusion  Our results demonstrated that the activation of RP11-115N4.1 can significantly increase the protein level of HSP70  via  binding to HNRNPH3, which may modulate the immune responses and related to URSA. Moreover, RP11-115N4.1 may be a novel etiological biomarker and a new therapeutic target for URSA.

frontiers in immunology

Long Noncoding RNA RP11-115N4.1 Promotes Inflammatory Responses by Interacting With HNRNPH3 and Enhancing the Transcription of HSP70 in Unexplained Recurrent Spontaneous Abortion