Ingestion of mast cell granules boosts macrophages and drives atypical programming

Background: Macrophages exhibit high heterogeneity and plasticity, which is essential for their multifaceted roles in host defense and tissue regeneration. Mast cells (MCs) respond rapidly to injury or infection by releasing intact secretory granules, thereby initiating and potentiating innate and adaptive immunity.
Objective: Because MCs reside in close proximity to macrophages in the skin, we decoded the impact of exocytosed MC granules (MCGs) on macrophage phenotype and function.
Methods: We tracked the fate of MCGs and studied their specific effects on macrophage plasticity and functional characteristics in vivo and in vitro in mouse and human samples using advanced imaging, functional assays, and transcriptomic profiling.
Results: We found that intact MCGs are engulfed by macrophages in vivo in murine models and in vitro. MCG ingestion boosted macrophage functional capacities and resulted in an atypical plasticity that contains both alternatively activated and classically activated macrophage features, suggesting increased efficiency in their multifaceted roles. In addition, the engulfment of intact MCGs by macrophages led to a specific transcriptome reprogramming. Importantly, both the process of MCG ingestion and its functional impact was confirmed with human MCs and macrophages in vitro and in situ in healthy human skin explants and in psoriatic patient lesional skin.
Conclusion: MCs enhance the function of macrophages and drive them to atypical polarization through granule-mediated intercellular communication. Our results suggest that beyond acute inflammation, MCs act as important controllers of host defense and integrity, supporting their emerging relevance as therapeutic targets.