ABSTRACT
The skin comprises tissue macrophages as the most abundant resident immune cell type. Their diverse tasks including resistance against invading pathogens, attraction of bypassing immune cells from vessels, and tissue repair require dynamic specification. Here, we delineated the postnatal development of dermal macrophages and their differentiation into subsets by adapting single-cell transcriptomics, fate mapping, and imaging. Thereby we identified a phenotypically and transcriptionally distinct subset of prenatally seeded dermal macrophages that self-maintained with very low postnatal exchange by hematopoietic stem cells. These macrophages specifically interacted with sensory nerves and surveilled and trimmed the myelin sheath. Overall, resident dermal macrophages contributed to axon sprouting after mechanical injury. In summary, our data show long-lasting functional specification of macrophages in the dermis that is driven by stepwise adaptation to guiding structures and ensures codevelopment of ontogenetically distinct cells within the same compartment.
Subject(s)
Cell Differentiation/immunology , Immunologic Surveillance , Macrophages/immunology , Nerve Regeneration , Skin/immunology , Skin/innervation , Animals , Animals, Newborn , Biomarkers , CX3C Chemokine Receptor 1/metabolism , Dermis/cytology , Dermis/immunology , Dermis/metabolism , Immunophenotyping , Macrophages/metabolism , Mice , Skin/cytologyABSTRACT
Immunity to mycobacteria involves the formation of granulomas, characterized by a unique macrophage (MΦ) species, so-called multinucleated giant cells (MGC). It remains unresolved whether MGC are beneficial to the host, that is, by prevention of bacterial spread, or whether they promote mycobacterial persistence. Here, we show that the prototypical antimycobacterial molecule nitric oxide (NO), which is produced by MGC in excessive amounts, is a double-edged sword. Next to its antibacterial capacity, NO propagates the transformation of MΦ into MGC, which are relatively permissive for mycobacterial persistence. The mechanism underlying MGC formation involves NO-induced DNA damage and impairment of p53 function. Moreover, MGC have an unsurpassed potential to engulf mycobacteria-infected apoptotic cells, which adds a further burden to their antimycobacterial capacity. Accordingly, mycobacteria take paradoxical advantage of antimicrobial cellular efforts by driving effector MΦ into a permissive MGC state.
Subject(s)
Giant Cells/microbiology , Macrophages/physiology , Mycobacterium/metabolism , Nitric Oxide/metabolism , Animals , Cell Differentiation , Cells, Cultured , DNA Damage , Genes, p53/physiology , Giant Cells/metabolism , Humans , Macrophages/microbiology , Mice , Mycobacterium/immunology , Nitric Oxide/biosynthesisABSTRACT
We report a 77-year-old man with a skin abscess caused by Actinomyces radingae. Targeted antibiotic therapy with amoxicillin/clavulanic acid for 6 weeks resulted in clearing of the infection. A. radingae is a rare pathogenic agent of skin and soft tissue infections. As with other Actinomyces infections, the early identification of the pathogen and specific antibiotic therapy is crucial for successful resolution of the infection because of the chronic course and the long treatment time needed. Usually, A. radingae is sensitive to ßlactam antibiotics.
Subject(s)
Abscess , Actinomyces , Actinomycosis , Anti-Bacterial Agents , Skin Diseases, Bacterial , Humans , Male , Aged , Abscess/microbiology , Abscess/drug therapy , Abscess/diagnosis , Actinomycosis/drug therapy , Actinomycosis/diagnosis , Actinomycosis/microbiology , Actinomycosis/pathology , Actinomyces/isolation & purification , Anti-Bacterial Agents/therapeutic use , Skin Diseases, Bacterial/microbiology , Skin Diseases, Bacterial/drug therapy , Skin Diseases, Bacterial/diagnosis , Amoxicillin-Potassium Clavulanate Combination/therapeutic use , Treatment OutcomeABSTRACT
Discussion on how antibiotic treatment routes Mycobacterium avium to phagolysosomes without eliciting an immune response in human macrophages.
Subject(s)
Immune Evasion/immunology , Macrophages/immunology , Macrophages/microbiology , Mycobacterium avium Complex/immunology , Mycobacterium avium-intracellulare Infection/immunology , HumansABSTRACT
The immune response to mycobacteria is characterized by granuloma formation, which features multinucleated giant cells as a unique macrophage type. We previously found that multinucleated giant cells result from Toll-like receptor-induced DNA damage and cell autonomous cell cycle modifications. However, the giant cell progenitor identity remained unclear. Here, we show that the giant cell-forming potential is a particular trait of monocyte progenitors. Common monocyte progenitors potently produce cytokines in response to mycobacteria and their immune-active molecules. In addition, common monocyte progenitors accumulate cholesterol and lipids, which are prerequisites for giant cell transformation. Inducible monocyte progenitors are so far undescribed circulating common monocyte progenitor descendants with high giant cell-forming potential. Monocyte progenitors are induced in mycobacterial infections and localize to granulomas. Accordingly, they exhibit important immunological functions in mycobacterial infections. Moreover, their signature trait of high cholesterol metabolism may be piggy-backed by mycobacteria to create a permissive niche.