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Makrophagendifferenzierung bei Hautinfektionen durch Staphylokokken

Fachliche Zuordnung Kinder- und Jugendmedizin
Förderung Förderung von 2015 bis 2024
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 283781347
 
Erstellungsjahr 2024

Zusammenfassung der Projektergebnisse

Here we dissected molecular mechanisms underlying the phenotypic adaptation of highly differentiated macrophages (Mac) to tissue niches, in particular after trauma and infection. First, we explored mechanisms steering Mac to upregulate the fractalkine receptor (CX3CR1) and to downregulate the mannose receptor (MR) when adapting to sensory nerves. We combined our ear model including the punching reaction, which we developed with the help of prior DFG funding, with multidimensional in vitro and in vivo approaches, involving primary Mac or induced pluripotent stem cells. Thus we identified infiltrating myeloid progenitor cells to approach sprouting axons of sensory nerves and - in a stepwise process – adopt a sensory nerve-associated Mac (sNAM)-like profile. Transcriptomic profiling of in-vitro-generated sNaM revealed over 700 of the differentially expressed genes to be related to TGF-β signalling. Accordingly, blocking of TGF-β receptor 2 and physical separation of cell types in transwell culture prevented immunophenotypic changes reminiscent of sNaM in direct co-cultures with neurones, while activating latent TGF-β in cultures induced them. TGF-β-activation was partly mediated by integrin subunit β5, which was highly upregulated on Mac in contact with sensory nerves. Following tissue injury, TGF-β-driven Mac specification mediated nerve regeneration, since disruption of TGF-β-mediated crosstalk in conditional mouse models delayed nerve regeneration after injury. Thus TGF-β governed long-term local specialization and bidirectional communication between Mac and sensory nerves. In extension of long term homeostatic niche adaptation, dermal Mac need to respond in an effective, yet balanced fashion to local tissue invasion of commensal bacteria like S. aureus. Using a strictly intradermal ear infection model we found that mice, which were previously infected with S. aureus, showed increased bacterial killing and improved healing upon a secondary infection which relied on reprogramming of bona fide tissue Mac. However, skin infection decreased Mac half-life, thereby limiting the duration of memory. Thus, resident dermal Mac were programmed locally during staphylococcal skin infection, independently of bone marrow-derived monocytes. This led to transiently increased resistance against a second infection. Underlying molecular mechanisms involve the cytokine granulocyte-Mac colony-stimulating factor (GM-CSF) produced by γδ T cells and hypoxic conditions in the dermis diverting Mac away from a homeostatic M-CSF- and HIF-1α-dependent program. This enables Mac to be metabolically rewired for maximal inflammatory activity, which requires expression of Irg1 and generation of itaconate, but not HIF-1α. This multifactorial Mac rewiring program was required for both the timely clearance of bacteria and for the provision of local immune memory. These findings indicated that immunometabolic conditioning enables dermal Mac to cycle between antimicrobial activity and protection against secondary infections.

Projektbezogene Publikationen (Auswahl)

 
 

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