Inflammation is a ubiquitous but poorly understood consequence of
spinal cord injury (SCI). The mechanisms controlling this response are unclear but culminate in the sequential activation of resident and recruited immune cells. Collectively, these cells can exert divergent effects on cell survival and tissue repair.
HMGB1 is a ubiquitously expressed
DNA binding protein and also a potent inflammatory stimulus. Necrotic cells release HGMB1, but
HMGB1 also is actively secreted by inflammatory macrophages. A goal of this study was to quantify spatio-temporal patterns of cellular
HMGB1 expression in a controlled mouse model of experimental SCI then determine the effects of
HMGB1 on post-SCI
neuroinflammation and recovery of function. We documented SCI-induced changes in nuclear and cytoplasmic distribution of
HMGB1 in various cell types after SCI. The data reveal a time-dependent increase in
HMGB1 mRNA and
protein with
protein reaching maximal levels 24-72 h post-injury then declining toward baseline 14-28 days post-SCI. Although most cells expressed nuclear
HMGB1, reduced nuclear labeling with increased cytoplasmic expression was found in a subset of CNS macrophages suggesting that those cells begin to secrete
HMGB1 at the injury site. In vitro data indicate that extracelluar
HMGB1 helps promote the development of macrophages with a neurotoxic phenotype. The ability of
HMGB1 to elicit neurotoxic macrophage functions was confirmed in vivo; 72 h after injecting 500 ng of recombinant
HMGB1 into intact spinal cord ventral horn, inflammatory CNS macrophages co-localized with focal areas of neuronal killing. However, attempts to confer neuroprotection after SCI by blocking
HMGB1 with a
neutralizing antibody were unsuccessful. Collectively, these data implicate
HMGB1 as a novel regulator of post-SCI
inflammation and suggest that inhibition of
HMGB1 could be a novel therapeutic target after SCI. Future studies will need to identify better methods to deliver optimal concentrations of
HMGB1 antagonists to the injured spinal cord.