Seminal studies in the past decade have classified macrophages into tissue-resident and inflammatory monocyte-derived macrophages based on their ontogeny and functions. Tissue-resident macrophages arise prenatally from embryonic precursors and maintain their numbers in adults via limited cell renewal independent of bone marrow input. Their precise functional role within tissues is modulated by a combination of ontogenic, transcriptional, epigenetic, tissue-specific and niche-specific cues.
A specialised subset of tissue-resident macrophages that reside along blood vessels; namely, perivascular macrophages (PVM) have been shown to be crucial for the maintenance of tissue homeostasis and the regulation of immune response. PVM are present in several tissues; for example, skin, muscle, mammary fat pad, brain, and tumours. However, how these cells develop and coordinate immune responses within these tissues is poorly understood.
Using cutting-edge intravital microscopy, our studies have highlighted that within cutaneous tissues, PVM play a crucial role in modulating the recruitment, migration, and function of various immune cell subsets. For example, during cutaneous bacterial infections, PVM derived chemotactic factors aid in the recruitment of neutrophils resulting in pathogen clearance. Nonetheless, L. major parasites utilise these pathways to enhance parasite survival. Post-infection, PVM rapidly phagocytose the parasites, leading to the parasite transformation and proliferation within the phagolysosomal compartment of these macrophages. Therefore, while PVM promote immune responses during bacterial infection they can be co-opted by other parasites during cutaneous infections.
While PVM regulate their cell numbers under homeostasis, their development during inflammation remains unclear. Using a large array of functional studies, we have identified and characterised a unique progenitor for tissue-resident macrophages residing within the adult bone marrow. These progenitor cells are ontogenically, transcriptionally and phenotypically distinct from known macrophage precursors, namely monocytes. Furthermore, we show that these progenitors arise very early during embryonic development and are distinct from the known embryonic macrophage precursors. Taken together, our work provides a new paradigm for studying the function of macrophage subsets in a context-dependent manner and identifies a novel pathway for the generation of tissue-resident macrophage populations.