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

Abstract

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.