Project description: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.
Project description: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.
Project description:Macrophages are strongly adapted to their tissue of residence. Yet, we know little about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches. Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity. Kupffer cell loss induced the tumor necrosis factor (TNF) and interleukin-1 (IL-1) receptor-dependent activation of stellate cells and endothelial cells, resulting in the transient production of chemokines and adhesion molecules orchestrating monocyte engraftment. Engrafted circulating monocytes transmigrated into the perisinusoidal space, and acquired the liver-associated transcription factors ID3 and LXRα. Coordinated interactions with hepatocytes induced ID3 expression, while endothelial cells and stellate cells induced LXRα via a synergistic NOTCH-BMP pathway. This study shows that the Kupffer cell niche is composed of stellate cells, hepatocytes and endothelial cells that together imprint the liver-specific macrophage identity.
Project description:Macrophages are strongly adapted to their tissue of residence. Yet, we know little about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches. Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity. Kupffer cell loss induced the tumor necrosis factor (TNF) and interleukin-1 (IL-1) receptor-dependent activation of stellate cells and endothelial cells, resulting in the transient production of chemokines and adhesion molecules orchestrating monocyte engraftment. Engrafted circulating monocytes transmigrated into the perisinusoidal space, and acquired the liver-associated transcription factors ID3 and LXRα. Coordinated interactions with hepatocytes induced ID3 expression, while endothelial cells and stellate cells induced LXRα via a synergistic NOTCH-BMP pathway. This study shows that the Kupffer cell niche is composed of stellate cells, hepatocytes and endothelial cells that together imprint the liver-specific macrophage identity.