Wang Hongyan/Hu Jin/Wei Bin discover potential treatments for traumatic brain injury

iNature traumatic brain injury (TBI) is the leading cause of morbidity and death in young adults around the world.

So far, clinical trials related to TBI treatment have proven frustrating.

This may be due to the failure to clarify the complex and multi-faceted pathogenesis of TBI.

On March 12, 2021, Wang Hongyan, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Hu Jin from Fudan University, and Wei Bin from Shanghai University, jointly published an online newsletter entitled "M-CSF, IL-6" in Science Advances , and TGF-β promoted generation of a new subset of tissue repair macrophage for traumatic brain injury recovery" research paper, which aims to identify key cytokines that are beneficial to TBI repair, and found that TBI patients with better outcomes can be found in cerebrospinal fluid Or the concentration of macrophage colony stimulating factor, interleukin 6 and transforming growth factor-β (called M6T) in plasma strongly increases.

Using TBI mice, the study found that M2-like macrophages, microglia and endothelial cells are the main sources of M6T production.

In addition to the in vivo tracking of mCherry + macrophages in the zebrafish model, it is confirmed that M6T treatment can accelerate the infiltration and polarization of blood-spreading macrophages to a part of tissue repair macrophages.
The expression of these repair proteins is related to microglia.
Cell-like genes can be used for neuroprotection, angiogenesis and cell migration.

The M6T treatment of TBI mice and zebrafish improved neurological function while preventing the aggravated brain damage caused by M6T.

Given the low concentration of M6T in some patients with poor prognosis, M6T treatment may repair TBI by generating a previously unidentified subset of tissue repair macrophages.

Traumatic head injury (TBI) is the leading cause of morbidity and death in young adults around the world.

So far, clinical trials related to TBI treatment have proven frustrating.

This may be due to the failure to clarify the complex and multi-faceted pathogenesis of TBI.

Mechanical damage to the central nervous system (CNS) can cause local inflammation and recruit immune cells after the injury.

Macrophages exhibit functional plasticity and heterogeneity under the influence of the inflammatory microenvironment.

According to their unique molecular and biological characteristics, macrophages are classified into pro-inflammatory macrophages and anti-inflammatory macrophages according to different local cytokines.

Inflammatory macrophages are usually stimulated by interferon-γ and Toll-like receptors or other pathogen-related molecular patterns to produce pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) And inducible nitrate oxide synthase.

In contrast, IL-4 and IL-13 induced macrophages by up-regulating the expression of arginase 1 (Fizz1), arginase 1 (Arg1) in chitinase 3-like 3 (Ym1 / CHI3l3) Shows anti-inflammatory activity.

Tissue repair macrophages produce vascular endothelial growth factor α (VEGF-α) to promote angiogenesis for repair, while resolving macrophages produce IL-10 and transforming growth factor β1 (TGF-β1) to limit inflammation.

Both tissue repair macrophages and resolving macrophages are believed to contribute to the regeneration of the central nervous system and brain repair after injury.

However, the underlying key issues have not been fully elucidated, especially what key cytokines and growth factors are induced during brain injury, and how do they affect the function of macrophages to repair the central nervous system? Answering these questions may help find potential new biomarkers for the diagnosis or treatment of TBI.

After brain injury, various cytokines or growth factors are released, which accelerate or inhibit the repair process.

IL-4 and IL-13 are typical cytokines that favor tissue repair macrophages in various injury models (including myocardial injury and skin injury).

However, it is not yet certain whether IL-4 and IL-13 are abundant in the injured brain.

Therefore, the combined use of cytokines/growth factors may provide a new treatment strategy for the treatment of TBI patients.

Although the functions of various cytokines have been studied in brain repair, the treatment of combined cytokines in TBI is still unclear.

In TBI patients, the study found that monocytes/macrophages in the blood circulation rapidly increase, and the concentration of TGF-β, macrophage colony stimulating factor (M-CSF) and IL-6 (called M6T) Both are significantly improved.

Using CD45.
1 or tdTomato + bone marrow (BM) adoptive transfer model and tracking mCherry + zebrafish macrophages in vivo, the study observed blood-derived macrophages migrating to the injury site, some of which showed microglia-like morphology .

M2-like macrophages and microglia are the main cell sources of M6T.
They also significantly enhance the production of Arg1, YM-1, Fizz1 and CCL2 at the injury site.

M6T therapy improved the neurological function of TBI mice.
The mice infiltrated macrophages guided by RNA sequencing (RNA-seq) showed gene expression patterns similar to local microglia, including angiogenesis, neuroprotection and migration A subset of functionally related genes.

Consistently, administration of specific antibodies targeting M6T in vivo aggravated brain damage in TBI mice.

The study jointly proposed the feedback between the M6T-rich microenvironment and changes in the fate of macrophage injury sites, which may help design new strategies for TBI treatment.

Reference message: https://advances.
sciencemag.
org/content/7/11/eabb6260