Habean, M. L. | Search bioRxiv

bioRxiv2024

BATF2 is a regulator of interferon-gamma signaling in astrocytes during neuroinflammation

Astrocytic interferon (IFN){gamma} signaling is associated with a reduction in neuroinflammation. We have previously shown that the benefits of astrocytic IFN{gamma} arise from a variety of mechanisms; however, downstream effectors responsible for regulating this protection are unknown. We address this by identifying a specific transcription factor that may play a key role in modulating the consequences of IFN{gamma} signaling. RNA-sequencing of primary human astrocytes treated with IFN{gamma} revealed basic leucine zipper ATF-like transcription factor (BATF)2 as a highly expressed interferon-specific gene. Primarily studied in the periphery, BATF2 has been shown to exert both inflammatory and protective functions; however, its function in the central nervous system (CNS) is unknown. Here, we demonstrate that human spinal cord astrocytes upregulate BATF2 transcript and protein in an IFN{gamma}-specific manner. Additionally, we found that BATF2 prevents overexpression of interferon regulatory factor (IRF)1 and IRF1 targets such as Caspase-1, which are known downstream pro-inflammatory mediators. We also show that Batf2-/- mice exhibit exacerbated clinical disease severity in a murine model of CNS autoimmunity, characterized by an increase in both CNS immune cell infiltration and demyelination. Batf2-/- mice also exhibit increased astrocyte-specific expression of IRF1 and Caspase-1, suggesting an amplified interferon response in vivo. Further, we demonstrate that BATF2 is expressed primarily in astrocytes in MS lesions and that this expression is co-localized with IRF1. Collectively, our results further support a protective role for IFN{gamma} and implicate BATF2 as a key suppressor of overactive immune signaling in astrocytes during neuroinflammation.

neuroscience↗

bioRxiv2023

Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. While the cytokine interferon (IFN){gamma} is classically described as deleterious in acute CNS autoimmunity, we and others have shown astrocytic IFN{gamma} signaling also has a neuroprotective role. Here, we performed RNA sequencing and ingenuity pathway analysis on IFN{gamma}-treated astrocytes and found that PD-L1 was prominently expressed. Using a PD-1/PD-L1 antagonist, we determined that apoptosis was reduced in leukocytes exposed to IFN{gamma}-treated astrocytes in vitro. To further elucidate the role of astrocytic IFN{gamma} signaling on the PD-1/PD-L1 axis in vivo, we induced the experimental autoimmune encephalomyelitis (EAE) model of MS in Aldh1l1-CreERT2, Ifngr1fl/fl mice. Mice with conditional astrocytic deletion of IFN{gamma} receptor exhibited a reduction in PD-L1 expression which corresponded to increased infiltrating leukocytes, particularly from the myeloid lineage, and exacerbated clinical disease. PD-1 agonism reduced EAE severity and CNS-infiltrating leukocytes. Importantly, PD-1 is expressed by myeloid cells surrounding MS lesions. These data support that IFN{gamma} signaling in astrocytes diminishes inflammation during chronic autoimmunity via upregulation of PD-L1, suggesting potential therapeutic benefit for MS patients.

neuroscience↗