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.