Interferon regulatory factors: Role in transcriptional regulation of macrophage plasticity and activation

The interferon regulatory factor (IRF) family of transcription factors was originally implicated in anti-viral responses and Type I interferon (IFN) production. Subsequent studies revealed their multifaceted role in regulation of anti-microbial responses and cell differentiation. In particular, IRF8 is now known as one of the major factors regulating myeloid cell growth and differentiation, while IRF5 and IRF4 are associated with M1 and M2 macrophage polarisation, respectively. In addition, IRF factors appear to provide a mechanism for conferring signal specificity to expression of immune genes regulated by NFκB. For example, IRF3, whose activation by upstream kinases occurs in response to TLR4 stimulation by lipopolysaccharide (LPS) and TLR3 stimulation by double stranded RNA (dsRNA), is not activated in many other NFκB inducing signalling pathways. Another emerging feature of the IRF family is that different members of the family seem to target specific gene subsets, with IRF3 being essential for anti-viral Type I IFN responses, and IRF5 playing a key role in induction of pro-inflammatory cytokines and chemokines. This chapter will discuss the multifaceted functions of IRF proteins in macrophage biology.