Sensory neurons shape macrophage identity via TGF-β signalling

Julia Kolter; Clarissa-Laura Döring; Samah Sarout; Sebastian Baasch; Lloyd Steele; Reem Alsumati; Gabriel Victor Lucena da Silva; Conceição Elidianne Aníbal Silva; Isadora Marques Paiva; Zohreh Mansoori Moghadam; Vitka Gres; Florens Lohrmann; Philipp Aktories; Theresa Buchegger; Mitchell Bijnen; Layal Doumard; Benjamin Voisin; Christelle Le Foll; Nico Lachmann; Melanie Greter; Katrin Kierdorf; Muzlifah A. Haniffa; Thiago M. Cunha; Vincent Flacher; Philipp Henneke

doi:10.1016/j.immuni.2025.08.004

ImmunologyImmunitySep 5, 2025

Peer-reviewed journal article

Sensory neurons shape macrophage identity via TGF-β signalling

Julia Kolter iD, Clarissa-Laura Döring, Samah Sarout, Sebastian Baasch iD, Lloyd Steele iD, Reem Alsumati, Gabriel Victor Lucena da Silva iD, Conceição Elidianne Aníbal Silva iD, Isadora Marques Paiva iD, Zohreh Mansoori Moghadam iD, Vitka Gres iD, Florens Lohrmann iD, Philipp Aktories iD, Theresa Buchegger, Mitchell Bijnen iD, Layal Doumard iD, Benjamin Voisin iD, Christelle Le Foll iD, Nico Lachmann iD, Melanie Greter iD, Katrin Kierdorf iD, Muzlifah A. Haniffa iD, Thiago M. Cunha iD, Vincent Flacher iD, Philipp Henneke iD

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Abstract

Macrophages play integral roles in maintaining homeostasis and function in their tissues of residence. In the skin, prenatally seeded and highly specialized macrophages physically interact with sensory nerves and contribute to their regeneration after injury. However, mechanisms underlying the development and maintenance of this potentially lifelong commitment of macrophages to nociceptors remain largely elusive. Here, we found that infiltrating myeloid progenitor cells approached the sprouting axons of sensory nerves and gradually adopted a nerve-associated macrophage-like profile. This change in identity was steered and maintained by the immediate microenvironment, in particular TGF-{beta}, which was locally activated by the physical interaction with nerves and integrin-mediated cleavage. Following injury, TGF-{beta} driven specification of macrophages essentially supported nerve regeneration. Overall, we identified TGF-{beta} as a central mediator governing local imprinting and long-term specialization of macrophages in the skin, providing insights into the bidirectional communication between macrophages and sensory nerves.