Doering, C.-L. | bioRxiv Science

bioRxiv2025

Sensory neurons shape macrophage identity via TGF-β signalling

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.

immunology↗

bioRxiv2025

Tissue imprinting defines functional mosaic of dermal macrophages

Dermal macrophages (macs) protect the skin from invading pathogens. They are derived from embryonic as well as hematopoietic progenitors. However, the functional impact of their diverse origin and the control networks defining different subsets remain unclear. Here, using multidimensional analysis of dermal macs, we reveal that the absence of circulating monocytes in interferon regulatory factor 8 (Irf8) deficient mice delays mac renewal during the steady state. Yet, the functional mosaic of dermal macs remains largely intact, i.e., major dermal mac subsets develop independently of monocyte replenishment. Thus, the tissue microenvironment is sufficient to induce alternative differentiation pathways and functional specialization of resident cells. Mycobacterial skin infection induces a steep increase in mac density due to monocyte-derived macs which execute urgent antibacterial functions and differentiate into site-adapted mac subsets in wildtype but not Irf8-/-mice, while long-term resident macs are required to initiate a tissue repair program already in early stages of infection. In summary, we introduce a model, where an intricate network of specialized mac subsets develops to meet microanatomical needs and external cellular input is required only during immunological emergency situations. HighlightsO_LIIrf8-/--driven monocytopenia has negligible impact on homeostatic dermal macrophage diversity. C_LIO_LIResident dermal macrophages have diverse specializations but remain flexible to adapt to challenges such as lacking monocyte influx C_LIO_LIBone marrow-derived macrophages differentiate into specialized resident cells, with microenvironmental cues overriding origin-dependent programming. C_LIO_LIIn chronic bacterial infections, distinct specialized bone-marrow-derived macrophages mount the defense, while resident macrophages activate a tissue-modifying program from early on. C_LI

immunology↗