Biological aging of CNS-resident cells alters the clinical course and immunopathology of autoimmune demyelinating disease
Jeffrey R. Atkinson, Andrew D. Jerome, Andrew R. Sas, Ashley Munie, Cankun Wang, Anjun Ma, William D. Arnold, Benjamin M. Segal
Jeffrey R. Atkinson, Andrew D. Jerome, Andrew R. Sas, Ashley Munie, Cankun Wang, Anjun Ma, William D. Arnold, Benjamin M. Segal
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Research Article Neuroscience

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 typically presents in the third or fourth decade, whereas 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, was more severe, and less likely to remit, in middle-aged compared with young adult mice. Donor T cells and neutrophils were more abundant, while B cells were relatively sparse, in CNS infiltrates of the older mice. Experiments with reciprocal bone marrow chimeras demonstrated that radio-resistant, nonhematopoietic cells played a dominant role in shaping age-dependent features of the neuroinflammatory response, as well as the clinical course, during EAE. Reminiscent of PMS, EAE in middle-aged adoptive transfer recipients was characterized by widespread microglial activation. Microglia from older mice expressed 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.

Authors

Jeffrey R. Atkinson, Andrew D. Jerome, Andrew R. Sas, Ashley Munie, Cankun Wang, Anjun Ma, William D. Arnold, Benjamin M. Segal

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Figure 6

GM-CSF promotes exacerbated EAE in middle-aged mice early, but not late, in the clinical course.

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GM-CSF promotes exacerbated EAE in middle-aged mice early, but not late,...
(A and B) CNS mononuclear cells were harvested from the spinal cords of young adult and middle-aged mice on day 10 after T cell transfer for analysis by flow cytometry. (A) Representative dot plots showing intracellular GM-CSF expression, gating on CD45.1+ donor CD4+ T cells. (B) Total number of GM-CSF+ donor T cells (left panel), and geometric mean fluorescence intensity (gMFI) of GM-CSF in donor T cells (right panel), isolated from the spinal cords of individual mice. Data were pooled from 2 independent experiments with 5–6 mice/group. (C) CD45+ mononuclear cells, FACS sorted from the spinal cords of young adult or middle-aged mice with EAE on day 6 after cell transfer, were analyzed by single-cell RNA sequencing (scRNA-Seq). The volcano plot shows gene expression changes, comparing young versus middle aged cells, within the CD4+ T cell cluster. Red dots represent genes that are below an adjusted P value of 0.05 and greater than an absolute log2-fold change of 0.25. Green dots show genes that meet the fold change threshold but not the P value threshold. Blue dots show manually selected genes to display. (D–F) Middle-aged mice were injected i.p. with anti–GM-CSF neutralizing antibody or control antibody every other day from the time of encephalitogenic T cell transfer onward (n = 14 mice/group; pooled from 2 independent experiments). Mice were scored for severity of neurological deficits on a daily basis while blinded to the identity of the experimental groups. (D) Mean clinical scores of mice in each group over time (left panel). AUC of individual mice (right panel). (E) Day of clinical disease onset posttransfer and (F) peak clinical disease scores of individual mice. Statistical significance was determined using the unpaired 2-tailed Student’s t test. *P < 0.05 or as indicated. Error bars indicate mean ± SEM.