Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis

Abstract

AbstractThe role of senescence in disease contexts is complex, however there is considerable evidence that depletion of senescent cells improves outcomes in a variety of contexts particularly related to aging, cognition, and neurodegeneration. Here, the effect of a bioinformatically-rationalized senolytic was tested in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS). Single-cell analysis from brain tissue isolated from mice subjected to EAE identified microglia with a strong senescence signature including the presence of BCL2-family member transcripts. Cells expressing Bcl2l1 had higher expression of pro-inflammatory and senescence genes than their negative counterparts in EAE, suggesting they may exacerbate inflammation. Notably, in human single-nucleus sequencing from MS, BCL2L1 positive microglia were strongly enriched in lesions with active inflammatory pathology, and likewise demonstrated increased expression of immune related genes suggesting they may contribute to the active lesion pathology and tissue damage in chronic active lesions. Employing a small molecule BCL2 inhibitor, Navitoclax (ABT-263), significantly reduced the presence of microglia in the EAE spinal cord, suggesting that these cells can be targeted by senolytic treatment. ABT-263 treatment had a profound effect on EAE mice, decreasing motor symptom severity, improving visual acuity, promoting neuronal survival, and decreasing white matter inflammation. Together, these results provide evidence to support the idea that senescent glia may exacerbate inflammation resulting in negative outcomes in neuroinflammatory disease and that removing them may ameliorate disease.