Oxidized phosphatidylcholines induce chronic neurodegeneration partly through IL-1β mediated positive feedback

Abstract

Oxidized phosphatidylcholines (OxPC) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPC contribute to the pathophysiology of P-MS is unclear. Here, we report that OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this new model, we found that while microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology in caspase 1/4 deficient mice and by blockade of IL-1R1 indicate IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPC and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization may be effective for treating P-MS.