Project Summary
Chronic neuroinflammation plays a central role in spinal cord injury (SCI) and SCI-induced secondary damage.
Although peripheral immune cells such as macrophages (Mf) and the resident microglia-mediated
neuroinflammatory cascade have been implicated in SCI, the mechanisms of peripheral Mf and residential
microglia cross talk and how their interaction controls microglia-mediated neuroinflammation remains largely
unknown. This gap in our knowledge is a significant barrier to mitigating inflammation-induced secondary
damage in SCI. We have shown that peripheral bone marrow-derived macrophages (BMDM¿) migrate to the
epicenter of the injured core, where they engulf myelin debris to become pro-inflammatory myelin-laden
macrophages (Mye-M¿), which occupy the entire epicenter of the injured area indefinitely. In contrast, residential
microglia are largely excluded from the injury epicenter, but are in close contact with Mye-M¿ and remain
chronically activated, suggesting that: 1) BMDMf, not microglia, may be the major scavenger cells for myelin
debris clearance from the lesion center, and 2) the cause of chronic microglial activation in the injured spinal
cord is constantly present. We also demonstrated that myelin debris contains significant quantities of microRNAs
(myelin-enriched miRs) and Mye-Mf secrete exosomes that contain abundant myelin-enriched miRs, which
are distinct from naïve-Mf secreted exosomes. We further showed that these Mye-Mf-derived exosomes can
transfer to microglia, promoting additional inflammatory responses in microglia. Consequently, our central
hypothesis is that infiltrated peripheral BMDMf engulf myelin debris and associated miRs and secrete exosomal
myelin-enriched miRs, which are then transferred to adjacent microglia to promote microglia-mediated
neuroinflammation in SCI. We will test our hypothesis by completing the following specific aims: 1) Investigate
how peripheral BMDMf regulate microglia-mediated neuroinflammation. 2) Investigate whether targeting
exosome-mediated communication between Mye-Mf and microglia influences microglial activation. This
research is innovative because exosomes are a unique way of exchanging integrated signals, and targeting
exosomes may represent a therapeutic strategy more advantageous than classical approaches aimed at
neutralizing single inflammatory molecules in SCI. This work is significant because our study can not only be
applied to SCI but also to other demyelinating diseases that generate myelin debris such as stroke and multiple
sclerosis, which account for 80% of the sources of paralysis. Our research will have the positive impact of
generating novel therapeutic targets for SCI treatment.
