Mast cells activated in vitro can modulate macrophage polarization and antibacterial responses

Abstract

Background: Mast cells and macrophages are tissue-resident immune cells frequently found in close proximity in barrier organs. Macrophages show high plasticity and microenvironmental factors, such as cytokines, can influence their phenotype. Mast cells are central in allergic reactions where allergens cause mast cell activation via antigen-specific IgE antibodies and the release of a multitude of inflammatory substances. While macrophages have clearly defined physiologic roles in tissue maintenance and host defense against microbes, biological mast cell functions are less well defined.

Objective: In the current study, we aimed to understand the interplay of mast cells and macrophages and how mast cell-released mediators can shape macrophage phenotype and function.

Methods: Using primary in vitro models of mast cells and macrophages combined with microscopic, functional, metabolic, genetic, and epigenetic analyses, we investigate the macrophage polarization effects of mast cell mediators produced on activation with IgE and antigen. We apply a macrophage engraftment strategy to explore potential in vivo implications of mast cell-mediated priming.

Results: We find that preformed and newly synthesized mediators released by activated mast cells shape a macrophage phenotype different from the classical M1/M2 macrophage paradigm. Exposure to supernatant of activated mast cells induces epigenetic reprogramming of macrophages. This profound priming effect strongly alters macrophage phagocytosis, cytokine production, and transcriptomic responses on secondary exposure to bacteria or their products. Importantly, in vivo transfer of primed macrophages also significantly affects the outcome of sterile inflammation and bacterial peritonitis.

Conclusion: Our study highlights the great potential of activated mast cells as directors of macrophage function.

Keywords: Allergy; IgE; LPS; activation; bacteria; degranulation; epigenetic; infection; macrophage; mast cell; polarization; priming.