The Role of Interferon Regulatory Factor 1 in Regulating Microglial Activation and Retinal Inflammation

Abstract

Microglia are resident immune cells in the central nervous system (CNS). Microglial activation plays a prominent role in neuroinflammation and CNS diseases. However, the underlying mechanisms of microglial activation are not well understood. Here, we report that the transcription factor interferon regulatory factor 1 (IRF1) plays critical roles in microglial activation and retinal inflammation by regulating pro- and anti-inflammatory gene expression. IRF1 expression was upregulated in activated retinal microglia compared to those at the steady state. IRF1 knockout (KO) in BV2 microglia cells (BV2ΔIRF1) created by CRISPR/Cas9 genome-editing technique causes decreased microglia proliferation, migration, and phagocytosis. IRF1-KO decreased pro-inflammatory M1 marker gene expression induced by lipopolysaccharides (LPS), such as IL-6, COX-2, and CCL5, but increased anti-inflammatory M2 marker gene expression by IL-4/13, such as Arg-1, CD206, and TGF-β. Compared to the wild-type cells, microglial-conditioned media (MCM) of activated BV2ΔIRF1 cell cultures reduced toxicity or death to several retinal cells, including mouse cone photoreceptor-like 661 W cells, rat retinal neuron precursor R28 cells, and human ARPE-19 cells. IRF1 knockdown by siRNA alleviated microglial activation and retinal inflammation induced by LPS in mice. Together, the findings suggest that IRF1 plays a vital role in regulating microglial activation and retinal inflammation and, therefore, may be targeted for treating inflammatory and degenerative retinal diseases.

YY1 Lactylation Aggravates Autoimmune Uveitis by Enhancing Microglial Functions via Inflammatory Genes

“…According to previous studies, IRF1 positively regulates microglial activation, amplifies retinal inflammation, and enhances the migratory abilities of multiple cancer cells. [ 37 , 38 , 39 ] IDO1 was closely related to the enhanced migration and proliferation of cancer cells and participates in several immune and inflammatory diseases. [ 40 , 41 , 42 , 43 ] SEMA4D reportedly activated microglia in neurodegenerative and infectious diseases.…”

Panobinostat, a Histone Deacetylase Inhibitor, Reduces LPS-Induced Expression of Inducible Nitric Oxide Synthase in Rat Immortalized Microglia HAPI Cells

“…IRF1 is a target gene of STAT1 and participates in LPS-induced iNOS expression. [18][19][20] LPS promoted IRF1 mRNA expression, and Pano suppressed LPS-induced IRF1 mRNA expression (Fig. 5A).…”

A Distinct Microglial Cell Population Expressing Both CD86 and CD206 Constitutes a Dominant Type and Executes Phagocytosis in Two Mouse Models of Retinal Degeneration

“…Despite recent studies using single-cell RNA sequencing to reveal various microglial cell subtypes and their functions, little is known about CD86 and CD206 in microglial cells as these studies mainly focused on functional and origin-related genes of microglial cells [ 41 , 42 , 61 ]. However, CD86 and CD206 are still used as M1/M2 markers in recent microglial cell studies [ 62 , 63 ], and thus the dominant role of CD86-, CD206-, and CD86/CD206-co-expressing microglial cells needs to be further evaluated. In this study, we sorted microglial cells using anti-CD206 antibody.…”