Macrophages associated with the peripheral nervous system are incompletely understood. In Immunity, Henneke and colleagues investigate the interactions between sensory nerves and CX3CR1hiCD206low sensory nerve-associated macrophages (sNAMs) in the dermis at steady state and after injury. Macrophages associated with β3-tubulin+ nerves at homeostasis, known to be of embryonic origin and capable of self-renewal, were tdTomato+GFP+ in Cx3cr1creER/GFP R26tdT/tdT mice (defined as resident sNAMs), whereas macrophages detected around the newly sprouted, post-injury dense axon network known as the ‘regeneration ring’ were tdTomato−GFP+ and were derived from hematopoietic stem cells (defined as recruited sNAMs). After injury, resident sNAMs, which expressed tissue residency genes, upregulated proliferation and DNA repair genes, whereas recruited sNAMs, which expressed migration and neurogenesis genes, upregulated an sNAM program. TGFβ from dorsal root ganglion neurons induced an sNAM profile, including upregulation of CX3CR1 and downregulation of CD206, in bone marrow-derived macrophages in vitro, and sNAMs expressed TGFβ-related genes in situ. Deletion of Tgfbr2 in sNAMs resulted in their loss, suggesting continuous dependency on homeostatic TGFβ signaling for self-maintenance and transcriptional identity, and impaired nerve sprouting post injury, suggesting sNAM adaptation to the sensory nerve niche is required for reinnervation after injury.
Original reference: Immunity https://doi.org/10.1016/j.immuni.2025.08.004 (2025)
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