Mast cells modulate macrophage biology through release of pre-stored CSF1.

Abstract

Background: Mast cells are tissue-resident immune cells present in connective tissues throughout the body. They exert diverse functions in immunity by rapidly releasing a plethora of preformed mediators, including proteoglycans, cytokines, and proteases, which are stored in cytoplasmic granules.

Objective: Our aim was to systematically and globally identify mast cell-released protein mediators and elucidate their functions.

Methods: We analysed the secretomes of antigen-activated primary mouse mast cells using quantitative mass spectrometry-based proteomics and conducted follow-up studies in vitro, ex vivo and using mast cell-specific genetic mouse models.

Results: We identified CSF1 as a novel preformed mast cell mediator present in the granules of all connective tissue-type mast cells. We further show that the mast cell secretome can induce macrophage differentiation and a unique polarisation pattern via CSF1 and other mediators. Mast cell-derived CSF1 has systemic functions, as mast cell-specific CSF1-deficient mice have lower serum CSF1 levels and reduced numbers of circulating monocytes. In addition, using an orthotopic transplantation-based melanoma mouse model, we show that loss of mast cell-derived CSF1 promotes cancer cell expansion. Finally, we demonstrate that CSF1 is also prestored and released by human mast cells.

Conclusion: CSF1 is an evolutionarily conserved, constitutive mast cell granule component. Mast cell degranulation induces macrophage differentiation and a unique polarisation state, the former being completely dependent on CSF1, while the latter is only modulated.