Therapeutic blockade of HMGB1 reduces early motor deficits, but not survival in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Abstract

Background Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease without effective treatment. The receptor for advanced glycation end products (RAGE) and the toll-like receptor (TLR) system are major components of the innate immune system, which have been implicated in ALS pathology. Extracellularly released high-mobility group box 1 (HMGB1) is a pleiotropic danger-associated molecular pattern (DAMP), and is an endogenous ligand for both RAGE and TLR4. Methods The present study examined the effect of HMGB1 inhibition on disease progression in the preclinical SOD1 G93A transgenic mouse model of ALS using a potent anti-HMGB1 antibody (2G7), which targets the extracellular DAMP form of HMGB1. Results We found that chronic intraperitoneal dosing of the anti-HMGB1 antibody to SOD1 G93A mice transiently improved hind-limb grip strength early in the disease, but did not extend survival. Anti-HMGB1 treatment also reduced tumour necrosis factor α and complement C5a receptor 1 gene expression in the spinal cord, but did not affect overall glial activation. Conclusions In summary, our results indicate that therapeutic targeting of an extracellular DAMP, HMGB1, improves early motor dysfunction, but overall has limited efficacy in the SOD1 G93A mouse model of ALS.

Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1G93Amouse model of amyotrophic lateral sclerosis

“…The present study clearly demonstrated a marked reduction in overall inflammatory markers in the spinal cord including decreases in pro-inflammatory cytokines TNF α and IL-1β, the RAGE ligand and danger-associated molecular pattern molecule HMGB1, innate immune receptors TLR4 and C5aR1, inflammasome component NLRP3, and an oxidative stress marker. This is consistent with many prior studies demonstrating these components play pathogenic roles in ALS disease progression [35,36,40-43,20,19,37,44]. Interestingly, genetic deletion of RAGE also resulted in a down-regulation of the complement components C1qb and C3.…”

“…It is now well documented that RAGE and its pro-inflammatory ligands are potentially involved in ALS, with evidence from both human patients and rodent models [6,10,11,13,20,19,12]. The present study further adds to this knowledge demonstrating alteration of RAGE mRNA expression in the spinal cord and skeletal muscle of multiple preclinical transgenic ALS mouse models including SOD1 G93A , TDP43 Q331K and TDP43 WTxQ331K mice, suggestive of a common activation pathway for RAGE upregulation in these models, that is independent to the underlying genetic driver of the disease.…”

“…Sections were then washed for 3 × 5 minutes in PBS, then mounted with Prolong Gold Anti-Fade medium containing 4, 6-diamidino-2-phenylindole (DAPI; Invitrogen, Eugene, OR, USA). Quantification of GFAP, CD11b and CD68 was performed on ∼18 to 21 lumbar spinal cord sections spaced 320µm apart and expressed as the percentage immunoreactive area per section [17,20]. Quantification was within the second lumbar dorsal root ganglia (L2) to the fifth lumbar dorsal root ganglia (L5), selected with the aid of the mouse spinal cord atlas [21].…”

Single‐cell deconstruction of post‐sepsis skeletal muscle and adipose tissue microenvironments

“…We observed acute (1 day) and chronic (1 month) DAMP transcript upregulation in both immune (dendritic cells, T‐cells, macrophages, and neutrophils) and non‐immune (fibroblasts, endothelial cells, and tissue progenitor cells) suggesting that low‐level tissue damage may drive local inflammation and persistent tissue dysfunction. Considering recent advances targeting specific DAMP molecules 47,48 or broad classes of pro‐inflammatory DAMPs 49 to mitigate acute sepsis mortality, 50 it would be interesting to determine the extent to which DAMP/PAMP reduction would aid post‐sepsis muscle and fat tissue repletion.…”

Targeting Inflammation Driven by HMGB1

“…There are also reported therapeutic failures with the m2G7 in preclinical trials. Administration of m2G7 in a mouse model of amyotrophic lateral sclerosis showed overall very limited efficacy (59).…”