CCL11 inhibits microglial reparative responses in aged mouse brains following intracerebral hemorrhage

Old age is a non-modifiable risk factor for poorer functional recovery following intracerebral hemorrhage (ICH). Levels of the aging factor CC-motif chemokine 11 (CCL11) increase in circulation with age, and CCL11 has the ability to penetrate the brain, where it attenuates homeostatic functions. Microglia are essential brain tissue macrophages, and their 'reparative' functions, such as phagocytosis and anti-inflammatory response, are critical for improved ICH outcomes. Here, we study the effect of systemic neutralization of CCL11 in aged mice, particularly on microglial gene expression changes following ICH injury.

We employed RNA-sequencing analysis of microglia collected after experimental ICH in a mouse blood injection model. To neutralize circulating CCL11, we intraperitoneally administered an anti-CCL11 antibody to 18-month-old male mice prior to ICH, isolated microglia from the ipsilateral hemisphere, and used the microglia for bulk RNA-sequencing analysis. Using primary microglia in cultures subjected to ICH-like injury, we also examined the effect of CCL11 on gene expression changes in microglia.

We found that sequestration of CCL11 in the circulation of aged mice prior to ICH upregulates the expression of microglial genes linked to pro-phagocytic, antioxidative, and anti-inflammatory signaling. In addition, we found that recombinant CCL11 administration downregulated the expression of these 'reparative' genes, impaired phagocytic activity, and exacerbated reactive oxygen species production in cultured microglia subjected to ICH-like injury.

These findings suggest that CCL11 mediates aging-induced microglial dysfunction, and that neutralization of CCL11 can be considered an approach for limiting ICH damage in aged populations by enhancing microglial 'reparative' functions.