Mast cells modulate macrophage biology through release of prestored CSF1.

Abstract

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. We sought to systematically and globally identify MC-released protein mediators and elucidate their functions. 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. 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. 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.