Elucidating the Role of Ezh2 in Tolerogenic Function of NOD Bone Marrow-Derived Dendritic Cells Expressing Constitutively Active Stat5b

Abstract

Tolerogenic dendritic cells (toDCs) are crucial to controlling the development of autoreactive T cell responses and the prevention of autoimmunity. We have reported that NOD.CD11cStat5b-CA transgenic mice expressing a constitutively active (CA) form of Stat5b under the control of a CD11c promoter are protected from diabetes and that Stat5b-CA-expressing DCs are tolerogenic and halt ongoing diabetes in NOD mice. However, the molecular mechanisms by which Stat5b-CA modulates DC tolerogenic function are not fully understood. Here, we used bone marrow-derived DCs (BMDCs) from NOD.CD11cStat5b-CA transgenic mice (Stat5b-CA.BMDCs) and found that Stat5b-CA.BMDCs displayed high levels of MHC class II, CD80, CD86, PD-L1, and PD-L2 and produced elevated amounts of TGFβ but low amounts of TNFα and IL-23. Stat5b-CA.BMDCs upregulated Irf4 and downregulated Irf8 genes and protein expression and promoted CD11c+CD11b+ DC2 subset differentiation. Interestingly, we found that the histone methyltransferase Ezh2 and Stat5b-CA bound gamma-interferon activated site (GAS) sequences in the Irf8 enhancer IRF8 transcription, whereas Stat5b but not Ezh2 bound GAS sequences in the Irf4 promoter to enhance IRF4 transcription. Injection of Stat5b-CA.BMDCs into prediabetic NOD mice halted progression of islet inflammation and protected against diabetes. Importantly, inhibition of Ezh2 in tolerogenic Stat5b-CA.BMDCs reduced their ability to prevent diabetes development in NOD recipient mice. Taken together, our data suggest that the active form of Stat5b induces tolerogenic DC function by modulating IRF4 and IRF8 expression through recruitment of Ezh2 and highlight the fundamental role of Ezh2 in Stat5b-mediated induction of tolerogenic DC function.

Identification of STAT5B as a biomarker for an early diagnosis of endometrial carcinoma

“…Moreover, STAT5B inhibited IgE-induced cytokine production and limited IgE production in vivo (Kiwanuka et al, 2021). Further, the activation of STAT5b induced dendritic cell tolerance in another study (Zerif et al, 2020). Despite these findings, further studies are needed to determine the immune infiltration associated mechanism of STAT5B in EC.…”

The Heightened Importance of EZH2 in Cancer Immunotherapy

“…174,175 Additionally, the recruitment of EZH2 by the active form of STAT5B modulates IRF4 and IRF8 expression to generate tolerogenic DC function. 176 As a result, little is known about how EZH2 might affect DC activity and how that might affect tumor immunity. 173,177 Understanding the impact of EZH2 on DCs is essential given the significance of DCs in anticancer immunity.…”

The role and mechanisms of polycomb repressive complex 2 on the regulation of osteogenic and neurogenic differentiation of stem cells

“…13 Interestingly, a previous study reports that PRC2-EZH2-modified and further repress inflammation and bone loss in prediabetic NOD mice. 71 But EZH2 inhibition increases bone density in adult mice and alleviates bone loss in ovariectomy osteoporosis mice model. 36 In addition, GSK126 attenuates bone loss in the ovariectomy osteoporosis mouse model by inhibiting EZH2.…”

“…Pre‐treatment with BMP2 and EZH2 inhibitor GSK126 upregulates the osteoblast‐related genes COL1A1, DLX5, IBSP, OCN, RUNX2 and SP7 expression in hBMSCs on 3D scaffolds in vitro and enhances vascularization but not bone formation in vivo, suggesting that EZH2 might react to multi‐facets of the osteogenesis genes which potentially support the maturation of the osteoblastic lineage 69,70 . EZH2 and STAT5b‐CA (constitutively active Stat5b) bind to IRF8 promoter in bone marrow‐derived dendritic cells (hBMDCs) and further repress inflammation and bone loss in prediabetic NOD mice 71 . But EZH2 inhibition increases bone density in adult mice and alleviates bone loss in ovariectomy osteoporosis mice model 36 .…”