Abstract
Macrophage colony-stimulating factor (M-CSF) is an important cytokine for monocyte/macrophage lineage. Secretory M-CSF (sM-CSF) and membrane-bound M-CSF (mM-CSF) are two major alternative splicing isoforms. The functional diversity of these isoforms in the activation of tumor-associated macrophages (TAMs), especially in lymphoma microenvironment, has not been documented. Here, we studied the effects of M-CSF isoforms on TAMs in xenograft mouse model. More infiltrating TAMs were detected in microenvironment with mM-CSF and sM-CSF. TAMs could be divided into three subpopulations based on their expression of CD206 and Ly6C. While sM-CSF had greater potential to recruit and induce differentiation of TAMs and TAM subpopulations, mM-CSF had greater potential to induce proliferation of TAMs and TAM subpopulations. Though both isoforms educated TAMs and TAM subpopulations to M2-like macrophages, mM-CSF and sM-CSF induced different spectrums of phenotype-associated genes in TAMs and TAM subpopulations. These results suggested the diverse effects of M-CSF isoforms on the activation of TAMs and TAM subpopulations in lymphoma microenvironments.
Highlights
Macrophage colony-stimulating factor (M-CSF), known as colony-stimulating factor-1 (CSF-1), is the key regulator for monocyte / macrophage lineage [1]
This observation was further verified by confocal microscopy analysis (Figure 2C, 2D). These results demonstrated that more tumor-associated macrophages (TAMs) were found in tumor microenvironment with mM-CSF or Secretory M-CSF (sM-CSF)
We compared the in vivo effects of mM-CSF and sM-CSF on TAMs to explore functional diversity between these isoforms on TAMs in a lymphoma xenograft mouse model
Summary
Macrophage colony-stimulating factor (M-CSF), known as colony-stimulating factor-1 (CSF-1), is the key regulator for monocyte / macrophage lineage [1]. By alternative splicing from a single gene, three biologically active isoforms, i.e. secretory (sM-CSF), membranebound (mM-CSF) and extracellular matrix or proteoglycan (PG-M-CSF), have been identified [2]. PG-M-CSF was suggested as an extracellular matrix storage form of sM-CSF [3]. SMCSF regulates cells nearby or in distance by autocrine, paracrine or endocrine mechanisms, whereas mM-CSF regulates physically contact cells by juxtacrine mechanism [4]. M-CSF isoforms show distinct characteristics in both physiological and pathological processes. Transgenic expression of mM-CSF only partly restored
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