TIMP-1 Mediates Inflammatory And Immune Response In AOXGD And The Function Of GAPDHS In Uveal Melanoma

PurposeAdult orbital xanthogranulomatous disease(AOXGD)is a rare non-Langerhans cell histiocytosis that seriously affects visual function and appearance.The mechanism of AOXGD is not clear.In our study,we collected 22 tissue specimens to detect the expression of TIMPs and MMPs that affect the homeostasis of extracellular matrix(ECM).We revealed the role of TIMP-1 that mediated inflammatory and immune response in AOXGD based on TIMP-1 highly expressed by macrophages to provide new ideas for the treatment of AOXGD.There is metabolic rearrangement in UM and UM cells preferred to exhibit high levels of glycolytic flux under the absence of oxygen or normal oxygen.Based on glycolytic enzymes,we clarified the role of highly expressed GAPDHS in UM and revealed the pathogenesis mechanism of GAPDHS in UM.Content and methods1.Collect data of 22 patients diagnosed as AOXGD.2.Q-PCR and immunohistochemistry were used to detect the expression of markers related to the homeostasis of ECM in AOXGD.3.Immunohistochemistry was used to detect the expression of IL-6 and JAK/STAT signaling pathway in AOXGD.4.Elisa was adopted to detect the relationship between TIMP-1 and JAK/STAT signaling pathway at the cellular level.5.Immunohistochemistry was used to examine the expression of markers of Th1 and Th17 cells in AOXGD.6.Q-PCR and Westernblot were performed to examine the expression of GAPDHS in UM.7.Clony-formation assay was performed to identify the functions of GAPDHS after knockdown and overexpression on UM progress.8.Westernblot and clony-formation assay were used to examine the relationship between SOX10 and GAPDHS.Achievement1.TIMP-1 and MMP-9 are highly expressed in AOXGD tissues while MMP-1 is lowly expressed,and ECM homeostasis is absent in AOXGD.2.IL-6 is highlyexpressed in AOXGD and mediates the overactivation of JAK/STAT signaling pathway in AOXGD,resulting in abnormal accumulation of TIMP-1 in AOXGD.3.Adaptive Th1 and Th17 cell immune response were participated in the development of AOXGD.4.GAPDHS was highexpressed and promote the tumorigenesis and regulated the glycolysis of UM.5.SOX10 regulate GAPDHS expression and glycolysis of UM and promote the proliferation of UM.Conclusion1.This study examined the expression of markers related to homeostasis ECM and identified the ECM homeostasis is absent in AOXGD.2.This study revealed the mechanism of IL-6~JAK2/STAT3 signaling pathway mediating TIMP-1 expression in AOXGD and proposed the activation of adaptive Th1 and Th17 cell immune response was involved in AOXGD.3.This study elucidate the function and mechanism that SOX10 regulated the expression of GAPDHS in UM.