IRF8: Mechanism of Action and Health Implications

Abstract

Interferon regulatory factor 8 (IRF8) is a transcription factor of the IRF protein family. IRF8 was originally identified as an essentialfactor for myeloid cell lineage commitment and differentiation. Deletion of Irf8 leads to massive accumulation of CD11b+Gr1+ immature myeloid cells (IMCs), particularly the CD11b+Ly6Chi/+Ly6G− polymorphonuclear myeloid-derived suppressor cell-like cells (PMN-MDSCs). Under pathological conditions such as cancer, Irf8 is silenced by its promoter DNA hypermethylation, resulting in accumulation of PMN-MDSCs and CD11b+ Ly6G+Ly6Clo monocytic MDSCs (M-MDSCs) in mice. IRF8 is often silenced in MDSCs in human cancer patients. MDSCs are heterogeneous populations of immune suppressive cells that suppress T and NK cell activity to promote tumor immune evasion and produce growth factors to exert direct tumor-promoting activity. Emerging experimental data reveals that IRF8 is also expressed in non-hematopoietic cells. Epithelial cell-expressed IRF8 regulates apoptosis and represses Osteopontin (OPN). Human tumor cells may use the IRF8 promoter DNA methylation as a mechanism to repress IRF8 expression to advance cancer through acquiring apoptosis resistance and OPN up-regulation. Elevated OPN engages CD44 to suppress T cell activation and promote tumor cell stemness to advance cancer. IRF8 thus is a transcription factor that regulates both the immune and non-immune components in human health and diseases.

Nuclear VANGL2 Inhibits Lactogenic Differentiation

“…STAT5 signaling also promotes proliferation through its upregulation of Cyclin D1 ( Ccdn1 ) 22 . IRF1 and IRF8 are also downstream targets of JAK/STAT 23, 24 , and associated with milk production 25 . We further saw a very strong, shared downregulation of polycomb repressive complex (PRC) 1 and PRC2 pathway components SUZ12, EZH2, MTF2 and RNF2 (Supplementary Figure 1K).…”

Nuclear VANGL2 Inhibits Lactogenic Differentiation

“…STAT5 signaling also promotes proliferation through its upregulation of Cyclin D1 (Ccdn1) [41]. IRF1 and IRF8 are downstream targets of JAK/STAT [42,43], and associated with milk production [44]. We further saw a very strong, shared downregulation of polycomb repressive complex (PRC) 1 and PRC2 pathway components SUZ12, EZH2, MTF2, and RNF2 (Supplementary Figure S2K).…”

Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas

“…As mentioned earlier, IRF8, which was shown to be significantly reduced in COVID-19, promotes macrophage and dendritic cell differentiation [151] and has a critical role in autophagy, antigen presentation, and clearing intracellular pathogens [90]. Autophagy controls MHC II antigen presentation and is crucial for boosting tolerance and anti-inflammatory processes by myeloid cells [67,91,101,152]. Still, this process is impaired when IRF8 is downregulated, preventing immune cells from responding to antigens.…”

“…IRF8 is a transcription factor that promotes macrophage and dendritic cell differentiation and is critical for the expression of autophagy-related genes, stress-induced autophagy regulation, antigen presentation, and clearance of intracellular pathogens [90,91]. Studies show that COVID-19 patients have significantly reduced expression of IRF8, which contributes to the impairment of immune responses mediated by autophagy pathways [89,92,93] and ultimately leads to increased viral proliferation and deregulated inflammatory pathways due to IRF8 s role in MDSC pathology, which is discussed below.…”