Sensory neurons imprint local macrophage identity via TGF-β [RNA-seq_in_vivo]

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 paradigmatic, 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-β, which was produced by neurons and locally activated by the physical interaction with nerves and integrin-mediated cleavage. Following injury, TGF-β driven specification of macrophages essentially supported nerve regeneration. Overall, we identified TGF-β 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. CX3CR1-creERT2/gfp R26-tdT/+ mice were induced with Tamoxifen, and 3 weeks later, left ears were punched. After 10 days, macrophages were sorted from left ear (injury) and right ear (homeostasis) for interstitial macrophages (GFP-/Tomato-), resident nerve-associated macrophages (GFP+/Tomato+) and recruited nerve-associated macrophages after injury (GFP+/Tomato-). All samples were taken from 3 different mice and analyzed by RNAseq.