Macrophages excite muscle spindles with glutamate to bolster locomotion

Yuyang Yan, Nuria Antolin, Luming Zhou, Luyang Xu, Irene Lisa Vargas, Carlos Daniel Gomez, Guiping Kong, Ilaria Palmisano, Yi Yang, Jessica Chadwick, Franziska Müller, Anthony M. J. Bull, Cristina Lo Celso, Guido Primiano, Serenella Servidei, Jean François Perrier, Carmelo Bellardita () and Simone Giovanni ()
Additional contact information
Yuyang Yan: Imperial College London
Nuria Antolin: University of Copenhagen
Luming Zhou: Imperial College London
Luyang Xu: Imperial College London
Irene Lisa Vargas: University of Copenhagen
Carlos Daniel Gomez: University of Copenhagen
Guiping Kong: Imperial College London
Ilaria Palmisano: Imperial College London
Yi Yang: Imperial College London
Jessica Chadwick: Imperial College London
Franziska Müller: Imperial College London
Anthony M. J. Bull: Imperial College London
Cristina Lo Celso: Imperial College London
Guido Primiano: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Serenella Servidei: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Jean François Perrier: University of Copenhagen
Carmelo Bellardita: University of Copenhagen
Simone Giovanni: Imperial College London

Nature, 2025, vol. 637, issue 8046, 698-707

Abstract: Abstract The stretch reflex is a fundamental component of the motor system that orchestrates the coordinated muscle contractions underlying movement. At the heart of this process lie the muscle spindles (MS), specialized receptors finely attuned to fluctuations in tension within intrafusal muscle fibres. The tension variation in the MS triggers a series of neuronal events including an initial depolarization of sensory type Ia afferents that subsequently causes the activation of motoneurons within the spinal cord1,2. This neuronal cascade culminates in the execution of muscle contraction, underscoring a presumed closed-loop mechanism between the musculoskeletal and nervous systems. By contrast, here we report the discovery of a new population of macrophages with exclusive molecular and functional signatures within the MS that express the machinery for synthesizing and releasing glutamate. Using mouse intersectional genetics with optogenetics and electrophysiology, we show that activation of MS macrophages (MSMP) drives proprioceptive sensory neuron firing on a millisecond timescale. MSMP activate spinal circuits, motor neurons and muscles by means of a glutamate-dependent mechanism that excites the MS. Furthermore, MSMP respond to neural and muscle activation by increasing the expression of glutaminase, enabling them to convert the uptaken glutamine released by myocytes during muscle contraction into glutamate. Selective silencing or depletion of MSMP in hindlimb muscles disrupted the modulation of the stretch reflex for force generation and sensory feedback correction, impairing locomotor strategies in mice. Our results have identified a new cellular component, the MSMP, that directly regulates neural activity and muscle contraction. The glutamate-mediated signalling of MSMP and their dynamic response to sensory cues introduce a new dimension to our understanding of sensation and motor action, potentially offering innovative therapeutic approaches in conditions that affect sensorimotor function.

Date: 2025
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DOI: 10.1038/s41586-024-08272-5

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