Macrophage differentiation in staphylococcal skin infection

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Staphylococcus aureus (S. aureus) is both a normal mucocutaneous colonizer in healthy people and a leading cause of soft tissue and bone infections and sepsis. Toll-like receptor dependent sensing of S. aureus by resident dermal macrophages (Mac) is key for a rapid and balanced immune response. In the outgoing funding period, we defined three ontogenetically and functionally discriminable Mac subtypes. A quantitatively small subtype of prenatally seeded Mac with high expression of CX3CR1, but not CD206, was highly adapted to sensory nerves and important for their regeneration (denomination „sNaM“). In contrast to sNaM, the two more frequent dermal Mac types share a common functional niche. CX3CR1-int Mac dynamically expand during staphylococcal infection and compensate for a loss in CX3CR1-low Mac. At the same time, the growth factor GM-CSF is induced and Mac are programmed towards the formation of Type-I-Interferons and antigen presentation. Finally, a staphylococcal infection induces local immune memory in Mac. It is the central hypothesis of this proposal, that the analysis of dermal macrophage types, as defined in the outgoing funding period, provides a keyhole for how Mac diversify into highly dedicated subsets, and how they maintain their population size and activity in homeostasis and after infectious or traumatic challenges. The following questions shall be addressed in this proposal: 1. What is the role of mannose receptor in Mac adaptation to the sensory nerve niche? 2. How does a staphylococcal skin infection induce immune memory in dermal Mac? 3. What is the role of metabolic changes in dermal Mac immunity to staphylococci?