Blocking LRP1 May Halt Inflammation, Promote Remyelination, Mouse Study Suggests
Blocking production of the low-density lipoprotein receptor-related protein 1 (LRP1) — involved in inflammatory and immune responses — specifically in myelin repair cells halts neuroinflammation and promotes myelin repair, a preclinical study shows.
These results, from two mouse models of multiple sclerosis (MS), shed light on the underlying mechanisms by which myelin repair cells contribute to myelin loss and cell damage upon neuroinflammation, and pinpoint LRP1-associated pathways as new potential therapeutic targets.
The study, “The active contribution of OPCs to neuroinflammation is mediated by LRP1,” was published in the journal Acta Neuropathologica.
In people with MS, the body’s immune system mistakenly recognizes myelin — the protective sheath around nerve fibers — as a foreign molecule and attacks it, causing inflammation and damage to brain nerve cells.
Upon myelin damage in the brain, immature, stem-like cells called oligodendrocyte precursor cells (OPCs) travel to the lesion site, where they mature into oligodendrocytes — myelin-producing cells capable of restoring the myelin sheath.
However, the myelin repair process is impaired in people with MS. Increasing evidence highlights that OPCs — once thought to have only a beneficial role in the process of myelin repair — play an active role in MS-associated myelin loss.
A previous study has shown that neuroinflammation hijacks OPCs not only to prevent their differentiation into myelin-producing cells, but also to promote further inflammation and immune attacks against myelin.
Researchers found that in an MS environment, OPCs acted like some immune cells, “ingesting” myelin molecules and presenting them to a specific type of immune T-cell known as CD8+ cells to induce immune reactions against them — a process called antigen presentation.
Researchers at University of Virginia School of Medicine (UVA) now have discovered that OPCs’ antigen presentation “behavior” in MS is dependent of LRP1, a protein located in their cell membrane.
LRP1 is known to be involved in several cellular processes, including intracellular signaling, inflammation, clearance of dead cells, and antigen presentation. Also, the suppression or genetic deletion of LRP1 has been shown to prevent “ingestion” of cells or molecules, and therefore to impair antigen presentation.
“Taken together, this evidence places LRP1 as a potential key player in the context of remyelination, but the contribution of LRP1 in OPCs during neuroinflammation remains unclear,” the researchers wrote.
First, the team confirmed the presence of LRP1 in OPCs in healthy human and mouse brains, and in two mouse models of MS associated with extensive myelin loss and induction of immune responses — the experimental autoimmune encephalomyelitis (EAE) model, and the cuprizone model (in which myelin loss is induced by the toxic agent cuprizone).
Researchers then analyzed the effects of genetically removing LRP1 specifically in OPCs in these mouse models. Mice lacking LRP1 in OPCs had normal myelin production, but had delayed disease onset and better clinical outcomes, compared to unaltered MS mice.
Further analysis showed this clinical benefit was not due to a direct effect on the OPCs maturation into myelin-producing cells, but was associated with a robust reduction in neuroinflammation, leading to increased neuroprotection and myelin repair.
LRP1-deficient OPCs had an impaired antigen presentation machinery, “suggesting a failure to propagate the inflammatory response, and thus promoting faster myelin repair and neuroprotection,” the researchers wrote.
The team proposed that the process of antigen “digestion” (including of myelin in MS) in OPCs is dependent of LRP1, and that these antigens are presented to CD8+ cells during myelin loss in MS, promoting further immune attacks against them.
Overall, these findings place “OPCs as major regulators of neuroinflammation in an LRP1-dependent fashion,” the team wrote.
While LRP1 is an attractive target to develop new therapeutic strategies for MS, the researchers emphasized that due to its involvement in several other cellular processes, identifying other molecules upstream or downstream of LRP1 that potentially could be targeted and cause less overall damage might be the way to go.
“It’s going to take a lot more work to translate these findings to any form of therapy,” Alban Gaultier, PhD, the study’s senior author, said in a press release. Gaultier is a researcher at UVA’s department of neuroscience and its center for brain immunology and glia (BIG).
“We are shining the light on this cell type that very few people have studied as part of the inflammatory response in the brain. More consideration should be given to the varied roles the progenitor cells play when focusing on finding a cure for MS,” Gaultier said.
Future studies are required to better understand the potential links between LRP1, CD8+ cells, and inflammation.