Differences in Cell-Intrinsic Inflammatory Programs of Yolk Sac and Bone Marrow Macrophages
Sara Elhag1, Christopher Stremmel1,2, Annette Zehrer3,4
1Medizinische Klinik und Poliklinik I, LMU Klinikum, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
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.
Insights
Macrophages originating from the yolk sac (YS) and bone marrow (BM) exhibit distinct cellular programs. These ontogeny-associated differences impact immune responses, particularly inflammasome activation and interleukin-1β production.
Area of Science:
- Immunology
- Developmental Biology
- Cell Biology
Background:
- Tissue-resident macrophages originate from diverse sources, including embryonic yolk sac (YS) hematopoiesis and postnatal bone marrow (BM) progenitors.
- The contribution of BM progenitors increases postnatally and during organ injury.
- Understanding the impact of macrophage ontogeny on their function is crucial due to tissue-specific modulation of macrophage phenotype.
Purpose of the Study:
- To investigate cell-intrinsic macrophage programs by analyzing differentiated macrophages derived from YS and BM progenitors.
- To elucidate the functional and molecular differences between macrophages based on their developmental origin.
Main Methods:
- Immortalization of hematopoietic progenitors from YS and BM using conditional HoxB8.
- In-depth functional and molecular analysis of differentiated macrophages from both origins.
Main Results:
- YS and BM macrophages share similarities in growth, differentiation, cell death susceptibility, and phagocytosis.
- Significant differences were observed in cell metabolism, inflammatory marker expression, and inflammasome activation.
- Reduced PYCARD (ASC) and CASPASE-1 protein levels in YS macrophages impaired interleukin-1β production.
Conclusions:
- Macrophage ontogeny is linked to distinct cellular programs and immune response profiles.
- These findings enhance the understanding of how macrophage functions are regulated and programmed based on their developmental origin.
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