Role of IRF4-Mediated Inflammation: Implication in Neurodegenerative Diseases

Abstract

Neuro-inflammation is a common feature of various central nervous system (CNS) disorders, including stroke, Alzheimer's disease, Multiple sclerosis, etc., and has a significant impact on the outcomes. Regulation of the immune response has therapeutic value. Interferon regulatory factor 4 (IRF4) is a hemopoietic transcription factor critical for activation of microglia/macrophages and modulation of inflammatory responses. The effects of IRF4 signaling on inflammation are pleiotropic, and vary depending on immune cell types and the pathological microenvironment that is regulated by both pro- and anti-inflammatory cytokines. Mechanistically, IRF4 is a quintessential 'context-dependent' transcription factor that regulates distinct groups of inflammatory mediators in a differential manner depending on their activation in different cell types including phagocytes, T-cell subtypes, and neuronal cells. In this review, we summarized the recent findings of IRF4 in the context of immune responses in different cell types with diverse pathological conditions. The primary goal of this review is to understand the signaling pathways and beneficial functions of IRF4, in hope of developing effective therapeutic strategies targeting the immune responses to neurodegenerative diseases.

Keywords: Autoimmunity; IRF4; Inflammation; Ischemic stroke; Neurodegeneration.

Figure 1:

Structural domain organization of IRF4. DBD: DNA binding domain, LKD: linker domain, CIAD: C- terminal interferon activation domain, AR: Auto-inhibitory region.

Figure 2:

Flow cytometric (FC) characterization of M2 microglia activation after stroke. (A) CD206 expression on gated microglia at 3d and 7d of stroke (left three plots). Mean fluorescence intensity (MIF) of CD206 on microglia showed CD206 significantly increased at 3d but decreased to baseline at 7d. P*<0.05; n=4~6/gp.

Figure 2:

Flow cytometric (FC) characterization of M2 microglia activation after stroke. (B) Levels of IRF4 mRNA in FC sorted microglia at 3d and 7d after stroke showing the same pattern as that of CD206 expression. P*<0.05; n=4~6/gp

Figure 3:

The role of IRF4 in mediating T-cell’s secretion of IL-6 and IL-17 in Crohn disease (CD). (A) IRF4 dependent mucosal IL-6 production in experimental colitis.

Figure 3(B):

Relationship between IRF4 and epigenetic regulation of CD.

Figure 4:

Role of IRF4 in inflammatory disease on immune cells. IRF4 affects development and differentiation of T-cells subtypes such as Th2 and Th17. IRF4 differentially regulates the pro- and anti-inflammatory cytokine levels in IBD via NOD2/ STAT3/RORγt signaling in naive T-cells, and mediates the differentiation of Th2 and Th17 cells via GLi1/NFATc1/NFATc2 and STAT3/RORγt/Blim1/ICOS pathway respectively in autoimmune diseases in a lineage specific manner. IRF4 promotes differentiation of T-reg cells via Foxp3/Blimp1/ICOS signaling in obesity induced inflammation. In CNS, IRF4-SRF and Jmjd3-IRF4 regulatory axis regulate the neuronal degeneration and microglial activation respectively in ischemic stroke and AD. IBD; Inflammatory bowel diseases, RA; Rheumatoid arthritis, CD; Crohn disease, EAE; Experimental Autoimmune Encephalomyelitis, SLE; systemic lupus Erythematosus (SLE), MS; Multiple sclerosis, AD; Alzheimer’s disease.