Immune cells play a surprising and critical role in controlling movement and linking neural activity to metabolic demands, concludes a groundbreaking study published in the journal Nature by researchers from the Faculty of Health and Medical Sciences, University of Copenhagen and Imperial College London. This discovery opens up exciting new avenues for treating movement disorders and metabolic diseases.

This study reveals for the first time that macrophages within muscle spindles actively participate in motor control through a rapid neurotransmitter-mediated mechanism, which is usually only associated with neurons, challenging the traditional view of macrophages as pure immune cells.

"This study adds a new dimension to how the brain integrates sensation and action by demonstrating that macrophages directly regulate their activity, coupling immune responses to motor function, while also linking energy requirements to neural responses during movement," says Carmelo Bellardita, associate professor and group leader at the Department of Neuroscience at the University of Copenhagen.

The muscle spindles where the macrophages are located are tiny sensors within the muscles that help the body monitor how stretched or tense the muscles are. These sensors play a crucial role in guiding movements. For example, if you touch your nose with your eyes closed, the muscle spindles detect the movement of the arm muscles and send signals to the brain. This feedback allows your brain to adjust and control the movement, ensuring that your hand reaches your nose accurately - even without the help of vision.

Using a combination of cross-genetic, optogenetic, and electrophysiological techniques in mice, the researchers showed how muscle spindle-resident macrophages activate sensation. "Macrophages act on neurons through glutamate signaling, influencing neural activity, muscle contraction, and movement," said Carmelo Bellardita.

Glutamate signaling is a fast-acting communication system typically associated with nerve cells that play a key role in basic brain functions such as memory, learning, and movement. These macrophages use glutamate to regulate sensation and activate muscles. In turn, muscle contraction produces glutamine, which reactivates the macrophages, creating a continuous feedback loop. This complex mechanism highlights the role of macrophages as key integrators of immune, sensory, and metabolic functions in motor control.

"The multiple roles of macrophages in the neural, metabolic, and immune systems may have profound consequences for different types of pathologies," says Carmelo Bellardita. In diseases such as stroke, Parkinson's disease, and diabetes, where inflammation, energy deficiency, and disrupted neural circuits exacerbate disease progression, targeting macrophage dysfunction may offer a new therapeutic avenue. By exploiting their ability to regulate neural activity, fine-tune energy balance, and repair tissue, these immune cells could become key players in strategies to slow degeneration, restore motor function, and improve metabolic health.

"This groundbreaking work not only reshapes our understanding of motor control but also lays the foundation for innovative treatments that address the interconnected nature of immune, neural, and metabolic dysfunction," says Carmelo Bellardita.

About the Faculty of Health and Medical Sciences, University of Copenhagen

The Faculty of Health and Medical Sciences at the University of Copenhagen is a leading academic institution committed to advancing the health sciences through innovative research and education.

Journal reference:

Yan, Y., et al. (2024). Macrophages stimulate muscle spindles with glutamate to enhance motility. Nature. doi.org/10.1038/s41586-024-08272-5.