Abstract
Background: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood. Methods: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages. Results: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1β production in response to canonical and non-canonical inflammasome activation. Conclusions: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions.
Highlights
Macrophages are key effectors of innate immunity
Cells were transduced with an estrogen-regulated Hoxb8 (ERHoxb8), allowing their maintenance and expansion at the progenitor level [11,15]
Previous studies reported successful conservation of the hematopoietic progenitor stage with the Hoxb8 system, but Hoxb8 cell lines of yolk sac (YS) macrophage progenitors have not been reported to date
Summary
Macrophages are key effectors of innate immunity They contribute to organ functions, the maintenance of tissue homeostasis and defense against pathogenic invasion [1]. In order to fulfill organ-specific functions, resident macrophages adopt distinct properties, e.g., clearance of surfactant by alveolar macrophages or breakdown of bone tissue by osteoclasts [2]. These functions are largely imprinted by the tissue environment. Despite the strong impact of the local milieu on macrophage identity, significant heterogeneity can be observed between individual macrophages inside the same tissue [5] This heterogeneity might be explained in part by different developmental origins of macrophage populations.
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