Nuclear Receptor Nur77 Deficiency Alters Dendritic Cell Function

Abstract

Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system. Proper function of DCs is crucial to elicit an effective immune response against pathogens and to induce antitumor immunity. Different members of the nuclear receptor (NR) family of transcription factors have been reported to affect proper function of immune cells. Nur77 is a member of the NR4A subfamily of orphan NRs that is expressed and has a function within the immune system. We now show that Nur77 is expressed in different murine DCs subsets in vitro and ex vivo, in human monocyte-derived DCs (moDCs) and in freshly isolated human BDCA1+ DCs, but its expression is dispensable for DC development in the spleen and lymph nodes. We show, by siRNA-mediated knockdown of Nur77 in human moDCs and by using Nur77−/− murine DCs, that Nur77-deficient DCs have enhanced inflammatory responses leading to increased T cell proliferation. Treatment of human moDCs with 6-mercaptopurine, an activator of Nur77, leads to diminished DC activation resulting in an impaired capacity to induce IFNγ production by allogeneic T cells. Altogether, our data show a yet unexplored role for Nur77 in modifying the activation status of murine and human DCs. Ultimately, targeting Nur77 may prove to be efficacious in boosting or diminishing the activation status of DCs and may lead to the development of improved DC-based immunotherapies in, respectively, cancer treatment or treatment of autoimmune diseases.

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

“…PDGF and hypoxia induce Nr4a3 in VSMCs [35,36]. Nr4a3 promotes proliferation by inducing Cyclin D1, Cyclin D2 and PCNA, which effect was lost with siNr4a3 treatments [35,36,37]. While Nr4a1 and Nr4a2 are protective against hypertrophy and excess muscle tissue growth, Nr4a3 promotes proliferation.…”

NCoR1 and SMRT fine-tune inflammatory versus tolerogenic balance in dendritic cells by differentially regulating STAT3 signaling

“…Therefore, we used an alternative approach. It has been reported that 6-mercaptopurine (6-MP) induces the expression of NR4A1 in cells [18]. Therefore, we used 6-MP to enhance the expression of Nr4a1 in SMRT depleted cDC1 to see if it can complement the IL-10 expression.…”

“…NR4A1 has been reported to positively regulate mTOR activity and thereby STAT3 phosphorylation and IL-10 expression [46]. It is also shown that deficiency of NR4A1, a member of the nuclear receptor superfamily, leads to enhanced production of IL-6, TNF-α, and IL-12 in both human and murine dendritic cells [18]. Similarly, peroxisome proliferator-activated receptor (PPAR-α) also exerts anti-inflammatory effects on monocytes and macrophages [47].…”

“…NURR-77 controls production of IL-6, TNF-α, and IL-12 in both human and murine dendritic cells [18]. Similarly, peroxisome proliferator-activated receptor (PPAR-γ) also exerts anti-inflammatory effects in monocytes and macrophages [18]. Although TFs and NRs lead to activation of transcription, their activity is tightly regulated by a network of co-regulators, including co-activators and co-repressors.…”

The Importance of Regulation in Natural Immunity to HIV

“…Importantly, studies of mouse Ly6C low monocytes, which are considered to be the murine analogs of human non-classic monocytes, whereas Ly6C hi correspond to classic monocytes, demonstrated that the transition from Ly6C hi to Ly6C low monocytes depends on NR4A1 expression [ 143 ], which is necessary for the generation and survival of Ly6C low monocytes, which are being reduced by 90% in NR4A1-deficient mice [ 144 ]. Also, it has been shown that increased NR4A1 expression levels lead to diminished MoDC and T-cell activation [ 145 ]. Furthermore, recent studies with NR4A3-deficient mice show that NR4A3 expression is required to skew monocyte differentiation toward MoDCs and allows the acquisition of migratory characteristics required for MoDC function [ 146 ].…”