The Transcription Factor IRF8 Activates Integrin-Mediated TGF-β Signaling and Promotes Neuroinflammation

Abstract

SUMMARY Recent epidemiological studies have identified interferon regulatory factor 8 (IRF8) as a susceptibility factor for multiple sclerosis (MS). However, how IRF8 influences the neuroinflammatory disease has remained unknown. By studying the role of IRF8 in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we found that Irf8−/− mice are resistant to EAE. Furthermore, expression of IRF8 in antigen presenting cells (APCs, such as macrophages, dendritic cells and microglia), but not in T cells, facilitated disease onset and progression through multiple pathways. IRF8 enhanced αvβ8 integrin expression in APCs and activated TGFβ signaling leading to T helper 17 (Th17) cell differentiation. IRF8 induced a cytokine milieu that favored growth and maintenance of Th1 and Th17 cells, by stimulating interleukin-12 (IL12) and IL23 production, but inhibiting IL27 during EAE. Finally, IRF8 activated microglia and exacerbated neuroinflammation. Together, this work provides mechanistic bases by which IRF8 contributes to the pathogenesis of MS.

Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells

“…Neuroinflammation constitutes a fundamental process involved in the physiopathology of neurodegenerative disorders, including Parkinson's disease (PD) (Barcia et al 2012), Alzheimer's disease (AD) (Yoshiyama et al 2007), amyotrophic lateral sclerosis (ALS) (Frakes et al 2014) and multiple sclerosis (MS) (Yoshida et al 2014). Microglial cells play a central role in neuroinflammation, and thereby the functional phenotype acquired by these cells determines whether surrounding neurons survive or die.…”

Transcription factor IRF8 plays a critical role in the development of murine basophils and mast cells

“…The IRF8-GFP chimera protein is as functional as untagged IRF8, 38 and the knock-in mice showed no abnormality in hematopoiesis. 26,39 Somewhat unexpectedly, IRF8 expression, judged by GFP intensity, was not detectable in basophils in the bone marrow, spleen, and peripheral blood, or in mast cells in the peritoneal cavity, although it was abundant in B cells ( Figure 3A). Neutrophils and eosinophils did not express IRF8 either, consistent with previous reports.…”

Cutting Edge: ACVRL1 Signaling Augments CD8α+ Dendritic Cell Development

“…BMP7 signaling was reported to play a critical role in LC development (11). A recent study (13) (14) recently reported that Irf8 expression leads to an increase in Id2 transcript levels. These findings suggest that Irf8 may play an important role in controlling TGF-b signaling in DCs.…”

“…TGF-b1 was reported to upregulate Irf8 during DC development (12). Irf8 was shown to enhance transcription of Itgb8 gene that converts latent TGF-b to the active form at the interface of APCs and naive T cells (13). We analyzed the role of Irf8 in the regulation of TGF-b/BMP signaling in DCs using a commercially available PCR-based array specific to mouse TGFb/BMP signaling pathway genes.…”