Forkhead transcription factor FOXO3a mediates interferon‐γ‐induced MHC II transcription in macrophages

Abstract

Summary Macrophages are professional antigen‐presenting cells relying on the expression of class II major histocompatibility complex (MHC II) genes. Interferon‐γ (IFN‐γ) activates MHC II transcription via the assembly of an enhanceosome centred on class II trans‐activator (CIITA). In the present study, we investigated the role of the forkhead transcription factor FOXO3a in IFN‐ γ‐induced MHC II transcription in macrophages. Knockdown of FOXO3a, but not FOXO1 or FOXO4, diminished IFN‐γ‐induced MHC II expression in RAW cells. On the contrary, over‐expression of FOXO3a, but neither FOXO1 nor FOXO4, enhanced CIITA‐mediated trans‐activation of the MHC II promoter. IFN‐γ treatment promoted the recruitment of FOXO3a to the MHC II promoter. Co‐immunoprecipitation and RE‐ChIP assays showed that FOXO3a was a component of the MHC II enhanceosome forming interactions with CIITA, RFX5, RFXB and RFXAP. FOXO3a contributed to MHC II transcription by altering histone modifications surrounding the MHC II promoter. Of interest, FOXO3a was recruited to the type IV CIITA promoter and directly activated CIITA transcription by interacting with signal transducer of activation and transcription 1 in response to IFN‐γ stimulation. In conclusion, our data unveil a novel role for FOXO3a in the regulation of MHC II transcription in macrophages.

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

“…RFXAP, as a vital transcription factor for major histocompatibility complex (MHC) class II. It was revealed to downregulate the expression of MHC class II in DCs (Ding et al, 2015) and macrophages (Wu et al, 2019), resulting inhibition of CD4 + T cells infiltration (Surmann et al, 2015). It was associated with survival outcomes in solid tumors (Surmann et al, 2015;Ding et al, 2018).…”

“…On the contrary, increased abundance of M1-type macrophages, and CD8 + T cells were associated with favorable survival outcomes. As mentioned above, the six risk genes can not only have intrinsic roles in tumor growth and apoptosis (i.e., Guo and Dixon, 2016;Chen et al, 2019;Jego et al, 2019), but also serve as the immune-regulatory factors via antigen-presenting cells (APCs) and effector T lymphocytes (Borrego et al, 2006;Surmann et al, 2015;Ling et al, 2017;Zhu et al, 2018;Chen et al, 2019;Wu et al, 2019). Hence, it is worthwhile to explore the relationship between the risk groups and infiltrative immune cells in primary LGG.…”

Leishmania amazonensis Subverts the Transcription Factor Landscape in Dendritic Cells to Avoid Inflammasome Activation and Stall Maturation

“…For example, decreased expression of the TNF gene correlates with decreased expression of the NFATC1 and NFATC2 transcription factors that regulate key DC immune functions ( Figures 7A1-5) (78). Likewise, coordinated down-modulation of the MHC Cl II genes H2-Aa, H2-Oa, H2-Ob, H2-DMb2, and H2-DMa ( Figure 7A) correlates with reduced expression of (i) the Class II Major Histocompatibility Complex Transactivator (CIITA) essential for transcriptional activity of the MHC class II promoter (79), (ii) the Forkhead transcription factor FOXO3a that is a key component of the MHC II enhanceosome (80), and (iii) regulatory factor Xassociated protein (RFXAP) that binds to the X-box of MHC II promoters (79). These simple regulatory relationships are likely part of more complex regulatory cascades and networks, as suggested by the down-regulation of CIITA itself that could result from the reduced expression of the ETS-domain transcription factor SPI-1 (81) ( Figure 7A).…”

Exploring the therapeutic potential of forkhead box O for outfoxing COVID-19

“…As has been discussed earlier, FoxOs negatively impact the activation of IRFs and the subsequent IFN response. FoxO3 silencing reportedly stifled IFN-γ-associated major histocompatibility complex (MHC) II expression whereas FoxO3 upregulation stimulated cytotoxic trans -activator (CIITA)-induced trans -activation of the MHC II promoter [ 84 ]. Since CIITA has been implicated in resisting the endosomal entry of SARS-CoV-2, modulation of the FoxO3- CIITA signalling is likely to aid in managing the viral infection [ 85 ].…”