Mast cells modulate macrophage biology through release of prestored CSF1

Abstract

Background: Mast cells (MCs) 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: We sought to systematically and globally identify MC-released protein mediators and elucidate their functions.

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

Results: We identified CSF1 as a novel preformed MC mediator present in the granules of all connective tissue MCs. We further show that the MC secretome can induce macrophage differentiation and a unique polarization pattern via CSF1 and other mediators. MC-derived CSF1 has systemic functions, because MC-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 MC-derived CSF1 promotes cancer cell expansion. Finally, we demonstrate that CSF1 is also prestored and released by human MCs.

Conclusions: CSF1 is an evolutionarily conserved, constitutive MC granule component. MC degranulation induces macrophage differentiation and a unique polarization state, the former being completely dependent on CSF1, whereas the latter is only modulated.

Keywords: CSF1; mast cell; mast cell mediator; melanoma; proteome.