Regulating IRFs in IFN Driven Disease

Abstract

The Interferon regulatory factors (IRFs) are a family of transcription factors that play pivotal roles in many aspects of the immune response, including immune cell development and differentiation and regulating responses to pathogens. Three family members, IRF3, IRF5, and IRF7, are critical to production of type I interferons downstream of pathogen recognition receptors that detect viral RNA and DNA. A fourth family member, IRF9, regulates interferon-driven gene expression. In addition, IRF4, IRF8, and IRF5 regulate myeloid cell development and phenotype, thus playing important roles in regulating inflammatory responses. Thus, understanding how their levels and activity is regulated is of critical importance given that perturbations in either can result in dysregulated immune responses and potential autoimmune disease. This review will focus the role of IRF family members in regulating type I IFN production and responses and myeloid cell development or differentiation, with particular emphasis on how regulation of their levels and activity by ubiquitination and microRNAs may impact autoimmune disease.

Keywords: E3 ligase; interferon; microRNA; monocyte; ubiquitin.

Figure 1

Overview of RNA/DNA sensing pathways. E3 ligases and microRNAs regulating IRF family members are highlighted in text boxes. Green text box for positive regulators and red for negative regulators.

Figure 2

Overview of signaling downstream of the IFN-alpha receptor. microRNAs targeting IRF9 are highlighted in the text box.

Figure 3

Overview of IRF involvement in myeloid cell development and macrophage differentiation. E3 ligases and microRNAs regulating IRF family members are highlighted in text boxes. Green text box for positive regulators and red for negative regulators. CMP, common myeloid progenitor; CLP, common lymphoid progenitor; Mo, Monocyte; Neut, Neutrophil; DC, Dendritic cell; MΦ, macrophage.