Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease

Abstract

Biological aging is the strongest factor associated with the clinical phenotype of multiple sclerosis (MS). Relapsing remitting MS (RRMS) typically presents in the third or fourth decade, while the mean age of presentation of progressive MS (pMS) is 45 years old. Here we show that experimental autoimmune encephalomyelitis (EAE), induced by the adoptive transfer of encephalitogenic CD4+ Th17 cells, is more severe, and less like to remit, in middle-aged compared with young adult mice. Donor T cells and neutrophils are more abundant, while B cells are relatively sparse, in central nervous system (CNS) infiltrates of the older mice. Experiments with reciprocal bone marrow chimeras demonstrate that radio-resistant, non-hematopoietic cells play a dominant role in shaping age-related features of the neuroinflammatory response, as well as the clinical course, during EAE. Reminiscent of pMS, EAE in middle-aged adoptive transfer recipients is characterized by widespread microglial activation. Microglia from older mice express a distinctive transcriptomic profile, suggestive of enhanced chemokine synthesis and antigen presentation. Collectively, our findings suggest that drugs that suppress microglial activation, and acquisition or expression of aging-associated properties, may be beneficial in the treatment of progressive forms of inflammatory demyelinating disease.