Immune Cell Protein CD36 Shows Potential as Therapeutic Target, Study Suggests

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by Steve Bryson, PhD |

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For the first time, scientists have shown that a protein known as CD36 on the surface of some immune cells is crucial for clearing myelin debris and suppressing nerve cell inflammation in disorders such as multiple sclerosis (MS), according to a new study.

Based on these findings, the researchers suggested that “targeting CD36 holds therapeutic promise for demyelinating disorders such as MS.”

The study, “CD36-mediated uptake of myelin debris by macrophages and microglia reduces neuroinflammation,” was published in the Journal of Neuroinflammation.

MS is an autoimmune disease in which the immune system mistakenly attacks myelin, the fatty protective coating that covers nerve fibers. A hallmark of MS is the abundance of phagocytes (a type of white blood cell) that contain fragments of myelin in active lesions. Phagocytes represent a group of immune cells that normally protect the body by engulfing (eating) harmful invaders such as bacteria. 

While the uptake of myelin by phagocytes was initially thought to underlie the degradation of myelin, recent evidence has indicated that clearing myelin debris by phagocytes is also necessary for the repair of the central nervous system (consisting of the brain and spinal cord). 

A protein receptor on the surface of phagocytes, called CD36, plays an essential role in the uptake of fatty substances (fatty acids) into cells. CD36 deficiency in mice and humans has been shown to decrease fatty acid uptake in muscle and fat cells.

However, how CD36 is involved in the uptake of fatty myelin by phagocytes, and its role in MS, remains unclear. 

To better understand the function of CD36, a team led by researchers at the Hasselt University, in Belgium, conducted a study using cell-based tests as well as a mouse model with MS-like autoimmunity called the experimental autoimmune encephalomyelitis (EAE) model.

First, two phagocyte cells — called macrophages and microglia — were treated with myelin. Results showed that the activity of the CD36 gene, as well as the levels of CD36 protein, were significantly higher compared to untreated cells. 

Furthermore, in the EAE model, increased production of CD36 was found in fat-containing phagocytes within demyelinating lesions. Higher levels of CD36 were also found in myelin-containing phagocytes isolated from active lesions of MS patients. 

The uptake of myelin by macrophages and microglia resulted in the activation of a signaling pathway known as NRF2, which was responsible for the increased levels of CD36.

“Collectively, these findings show that myelin increases CD36 expression on gene and protein level in an NRF2-dependent manner,” the researchers wrote.

In turn, blocking CD36 decreased the ability of macrophages and microglia to uptake myelin fatty acids, which demonstrated that CD36 specifically controls the clearance of myelin debris.

Next, the team triggered inflammation in macrophages and microglia by the addition of lipopolysaccharide (LPS). The accumulation of myelin within these cells reduced inflammation, and blocking CD36 countered the anti-inflammatory impact of myelin.

“Pharmacological inhibition of CD36 promoted the inflammatory properties of myelin-containing macrophages and microglia in vitro,” the researchers wrote.

To validate these findings in vivo, the team tested the impact of blocking CD36 in EAE mice.

Compared to untreated mice, mice treated with a CD36-blocking chemical before EAE onset showed a worsened disease severity. An analysis of spinal cord lesions showed reduced levels of fat-containing phagocytes and increased activity against degenerated myelin.

Additionally, by measuring the levels of pro-inflammatory markers, the team found that blocking CD36 increased inflammation in the spinal cord of EAE mice.

In contrast, blocking CD36 after EAE onset did not affect disease severity once clinical symptoms were established.

Overall, these data suggested that “CD36-mediated clearance of myelin debris reduces neuroinflammation by driving phagocytes towards a less-inflammatory [state], in particular in early disease stages,” the team wrote.

“Our study provides the first evidence for an essential role of CD36 in the uptake of myelin and in controlling the inflammatory properties of phagocytes in demyelinating disorders,” the researchers concluded. “By mediating myelin debris clearance, CD36 induces a protective [state] in myelin-laden macrophages and microglia, and dampens EAE disease severity.”

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