Signaling protein CCL2 may promote nerve damage in NMOSD: Study

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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CCL2, a signaling protein that recruits immune cells to sites of injury, may play a key role in driving the nerve damage that results from antibodies against the aquaporin-4 (AQP4) protein in neuromyelitis optica spectrum disorder (NMOSD), a study suggests.

The signaling protein was found to be elevated in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — of NMOSD patients, particularly those with anti-AQP4 antibodies.

Also, in lab-grown cells and animal models, CCL2 suppression prevented AQP4 abnormalities and reduced cell death.

The findings suggest that CCL2 could be a promising therapeutic target in treating inflammatory diseases like NMOSD, the researchers noted.

The study, “Targeting chemoattractant chemokine (C–C motif) ligand 2 derived from astrocytes is a promising therapeutic approach in the treatment of neuromyelitis optica spectrum disorders,” was published in Frontiers in Immunology.

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Investigating role of CCL2 signaling protein in inflammation

Most cases of NMOSD, an autoimmune disease, are characterized by the abnormal production of self-reactive antibodies targeting AQP4, a water channel protein found at the surface of astrocytes, nervous system cells that help regulate and support nerve cells.

Circulating anti-AQP4 antibodies are thought to be able to enter the brain, where they bind to AQP4, driving astrocyte damage and leading to damaging inflammation, mainly in the spinal cord and optic nerve. The optic nerve relays signals between the eye and the brain.

A number of different cellular mechanisms might be involved in this damaging process, but to date none has been fully identified.

CCL2 is a molecule that helps coordinate the migration of immune cells during inflammation. Its activities have been implicated in a range of different inflammatory diseases, but its potential role in NMOSD remains unclear.

Now, a team of scientists in China investigated whether CCL2 might be involved in the inflammatory cascades that drive nervous system damage in NMOSD.

First, the team compared blood and CSF levels of CCL2 between 59 NMOSD patients and seven people with other non-inflammatory neurological conditions. Those patients served as a control group. Slightly more than half of the NMOSD patients (55.9%) — who had a mean age of 43.3 — had antibodies against AQP4.

The results showed that while blood CCL2 levels did not differ between the two groups of patients, the protein was significantly elevated in the CSF of people with NMOSD compared with controls. Also, NMOSD patients had significantly higher levels of CCL2 in their CSF than in their blood, but this difference was not observed in the control group.

Patients positive for anti-AQP4 antibodies had significantly higher CSF CCL2 levels, but comparable blood CCL2 levels, relative to those without such antibodies.

“Our results suggest that AQP4-IgG [anti-AQP4 antibodies] induces a significant CCL2 release in the CSF of NMOSD patients,” the researchers wrote.

Also, NMOSD patients had greater signs of blood brain barrier (BBB) disruption the relative to the control group. The BBB is a highly-selective membrane that prevents potentially harmful factors — like immune cells, antibodies, and microbes — from reaching the brain. Astrocytes play a key role in maintaining BBB integrity.

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CCL2 signaling protein may be ‘promising candidate target’ in NMOSD

To learn more, the researchers conducted a series of experiments using lab-grown rat astrocytes that were exposed to antibodies obtained from AQP4-IgG-positive NMOSD patients or to a healthy antibody.

The NMOSD antibodies led to the abnormal internalization of AQP4 proteins inside astrocytes, a process known to cause astrocyte damage. AQP4 levels on the cell surface were thus significantly reduced relative to astrocytes exposed to healthy antibodies.

Moreover, NMOSD antibodies promoted the release of a number of inflammatory molecules, including CCL2, and significantly reduced astrocyte survival.

When the researchers suppressed the production of CCL2 in lab-grown astrocytes, the NMOSD antibody-induced AQP4 abnormalities, enhanced astrocyte damage and death, and production of inflammatory molecules were reversed.

“Together, our results indicate that CCL2 may be involved in [NMOSD antibody-induced] damage in astrocytes,” the researchers wrote.

Similar findings were observed when CCL2 production was blocked specifically in astrocytes of a mouse model of NMOSD. While this model typically exhibits a loss of AQP4 from astrocytes’ surface and significant brain lesions, CCL2 suppression diminished these harmful changes.

Further experiments in lab-grown astrocytes showed that NMOSD antibodies activated certain inflammatory signaling pathways that appeared to be involved in promoting CCL2 production in astrocytes. By blocking these pathways, CCL2 production was decreased.

Overall, “our study provides new insights into the mechanism of [NMOSD antibody] damage to astrocytes,” the researchers wrote, noting that CCL2 appears to play a key role.

CCL2 may be a promising candidate target for novel drug discovery in the treatment of NMOSD.

Based on their findings, the scientists believe that antibody binding to AQP4 initiates inflammatory cascades that promote CCL2 release. In turn, CCL2 may recruit immune cells from the bloodstream that cause additional damage to astrocytes, nerve cells, and an already compromised BBB.

“The role of CCL2 in NMOSD [disease processes] needs further investigation, and CCL2 may be a promising candidate target for novel drug discovery in the treatment of NMOSD,” the team concluded.