Sensory neurons shape local macrophage identity via TGF-β signaling
Resident macrophages play integral roles in maintaining tissue homeostasis and function. In the skin, prenatally seeded, specialized macrophages patrol sensory nerves and contribute to their regeneration after injury. However, mechanisms underlying the long-lasting postnatal commitment of these nerve-associated macrophages remain largely elusive. Here, we found that traumatic injury induced recruitment of myeloid progenitor cells to the sprouting axons of sensory nerves, where they gradually acquired a nerve-associated macrophage-like profile. This identity change was driven and maintained by the immediate microenvironment, particularly by transforming growth factor-β (TGF-β), which was locally activated by the physical interaction with nerves and integrin-mediated cleavage, and by the neuropeptide calcitonin gene-related peptide (CGRP). Moreover, TGF-β-mediated macrophage specification was essential for proper nerve regeneration following injury. Overall, we identify TGF-β as a conserved, spatially regulated mediator governing local imprinting and long-term specialization of macrophages within the subtissular neuronal niche, offering insights into precise bidirectional neuro-immune crosstalk underlying skin homeostasis.
Authors
- Zohreh Mansoori Moghadam (ORCID: https://orcid.org/0009-0000-9751-7740)
- Philipp Henneke (ORCID: https://orcid.org/0000-0001-7314-7984)
- Benjamin Voisin (ORCID: https://orcid.org/0000-0003-1314-2908)
- Melanie Greter (ORCID: https://orcid.org/0000-0002-7220-5369)
- Philipp Aktories (ORCID: https://orcid.org/0000-0001-7379-791X)
- Theresa Buchegger
- Florens Lohrmann (ORCID: https://orcid.org/0000-0003-4428-3172)
- Nico Lachmann (ORCID: https://orcid.org/0000-0002-4245-1497)
- Conceição Elidianne Aníbal Silva (ORCID: https://orcid.org/0000-0001-5562-0205)
- Sebastian Baasch (ORCID: https://orcid.org/0000-0003-4378-3474)
- Vitka Gres (ORCID: https://orcid.org/0000-0002-5034-4691)
- Katrin Kierdorf (ORCID: https://orcid.org/0000-0002-9272-4780)
- Mitchell Bijnen (ORCID: https://orcid.org/0000-0003-2781-8702)
- Isadora Marques Paiva (ORCID: https://orcid.org/0000-0002-2741-150X)
- Vincent Flacher (ORCID: https://orcid.org/0000-0002-8648-2615)
- Gabriel Victor Lucena da Silva (ORCID: https://orcid.org/0000-0002-4435-659X)
- Muzlifah A. Haniffa (ORCID: https://orcid.org/0000-0002-3927-2084)
- Thiago M. Cunha
- Julia Kolter (ORCID: https://orcid.org/0000-0002-3268-8124)
- Christelle Le Foll (ORCID: https://orcid.org/0000-0002-6677-5488)
- Lloyd Steele (ORCID: https://orcid.org/0000-0003-4745-1338)
- Layal Doumard (ORCID: https://orcid.org/0000-0001-9407-7989)
- Christian Döring
- Reem Alsumati
- Samah Sarout
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Freiburg (DE)
- Universidade de São Paulo (BR)
- University of Zurich (CH)
- University Medical Center Freiburg (DE)
- Wellcome Sanger Institute (GB)
- Medizinische Hochschule Hannover (DE)
- Fraunhofer Institute for Toxicology and Experimental Medicine (DE)
- Immunologie, Immunopathologie et Chimie Thérapeutique (FR)
- Wellcome Centre for Mitochondrial Research (GB)
- Institut Polytechnique de Bordeaux (FR)
Publication Details
- Journal
- Immunity
- Published
- 2025-09-05
- DOI
- https://doi.org/10.1016/j.immuni.2025.08.004
- Citations
- 5
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 4.21
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Deutsches Zentrum für Lungenforschung
- Horizon 2020 Framework Programme
- European Research Council
- FP7 Coordination of Research Activities
- H2020 European Research Council
- H2020 Marie Skłodowska-Curie Actions