ABOVE: © istock.com, Dr_Microbe
Multiple sclerosis (MS) is a debilitating disease in which a patient’s immune system attacks the myelin protective coating around nerve cells, causing inflammation and disrupting communication to and from the brain. Evidence indicates that myeloid cells, components of the innate immune system, aid the initiation, progression, and remission of MS.1 However, scientists lacked methods to specifically track down myeloid cells as they turn from friend to foe and mount a more damaging immune response.
To fill this gap, researchers led by Michelle James, a radiochemist and neuropharmacologist at Stanford University, developed a novel PET tracer that targets the triggering receptor expressed on myeloid cells 1 (TREM1). They showed that in vivo TREM1 PET imaging allowed early disease detection and treatment monitoring in a mouse model of MS.2 Their findings, published in Science Translational Medicine, posit that TREM1 is an early marker of maladaptive innate immune responses, and highlight the biomarker’s potential use for monitoring disease progression and response to treatment in patients with the disease.
We literally did very excited happy dances in the preclinical imaging facility because the clarity of the images was just outstanding. For PET imaging, it is kind of rare to be able to see such clear-cut images where you do not even need quantification to see what is going on.
—Aisling Chaney, Washington University
“We have a way of lighting up where inflammation is in the whole body and brain in the context of MS,” said James, whose work focuses on the development of imaging agents for visualizing neuroimmune interactions. “We have never been able to do that before with such specificity.”
James did not initially focus on TREM1. The membrane receptor caught her attention when she was looking at a transcriptomic data set from her colleague Katrin Andreasson, a neurologist at Stanford University and coauthor of the study. The pair noticed that the expression of TREM1 was upregulated only when there was a more harmful immune response. “We thought, ‘wow, this could be a really great biomarker to tell us when there is something really bad occurring with the innate immune system in the context of diseases,’” James recalled.
To test this idea, the researchers focused on MS and used the experimental autoimmune encephalomyelitis (EAE) mouse model, which recapitulates important aspects of the disease such as muscle weakness and changes in the innate immune response. They developed a PET tracer by radiolabeling an anti-TREM1 antibody to specifically track down TREM1+ cells and used a PET imaging scanner to monitor the movement of myeloid cells through the animal’s body as disease progressed.
TREM1 was selectively expressed on peripheral myeloid cells in the EAE mouse model, and the researchers observed central nervous system infiltration of TREM1+ cells even in early stages of the disease, when mice showed few signs of loss of muscle function. “We literally did very excited happy dances in the preclinical imaging facility because the clarity of the images was just outstanding. For PET imaging, it is kind of rare to be able to see such clear-cut images where you do not even need quantification to see what is going on,” said Aisling Chaney, a neuroimaging biologist at Washington University and coauthor of the study.
The team also found that TREM1 PET signal showed higher sensitivity in detecting myeloid cell infiltration in the central nervous system of EAE mice than the current gold standard PET tracer, which is widely used to detect neuroinflammation in vivo.
Given the specificity of TREM1 to track harmful innate immune responses, the team next investigated if it could be used to indicate therapeutic response. They treated EAE-induced mice with the drug Siponimod and found a reduction in TREM1 PET signal in drug-treated mice. According to Chaney, these findings reveal that TREM1 could be used as a tool for screening different types of therapies, even those that do not directly target myeloid cells.
Using TREM1 knockout animals as controls in the imaging experiments also revealed a biological role for TREM1, Chaney explained. “In the TREM1 knockout animals that we induced EAE in, 50 percent of them just did not get sick or they just did not get sick at the same time point that we were looking at in the wild type animals,” she said. The team confirmed these observations by pharmacologically blocking TREM1 with LP17, a peptide decoy receptor known to attenuate TREM1 signaling, and observed reduced disease severity in EAE mice, suggesting therapeutic potential for targeting TREM1.
To establish TREM1’s clinical relevance, the researchers looked at brain biopsy samples from two patients with MS and examined the presence of TREM1+ cells. Since patients would benefit the most by detecting and diagnosing MS at early stages, the team looked for treatment-naïve, early-stage samples, which are not easy to obtain, James explained. The team found a high number of TREM1+ immune cells in MS brain lesions compared to non-MS samples, indicating that TREM1 could be used to monitor disease progression in humans.
The combination of multiple techniques strengthened the researchers’ findings, pointed out Daniele de Paula Faria, a molecular imaging researcher at the University of Sao Paulo, who was not involved in the research. “This is a complete study with promising results,” she added.
James and Chaney plan to continue exploring TREM1’s role in neurological disorders. “TREM1 had actually not been looked at in a lot of neurological disorders before,” Chaney said. “It is opening up a whole area of peripheral immune cells and their implications in neurodegenerative disorders.”
References
- Mishra MK, Yong VW. Myeloid cells - targets of medication in multiple sclerosis. Nat Rev Neurol. 2016;12(9):539-551.
- Chaney AM, et al. PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis. Sci Transl Med. 2023;15(702):eabm6267.
