Abstract
BackgroundMacrophages and fibroblasts are two major players in tissue repair and fibrosis. Despite the relevance of macrophages and fibroblasts in tissue homeostasis, remarkably little is known whether macrophages are able to influence the properties of fibroblasts. Here we investigated the role of paracrine factors secreted by classically activated (M1) and alternatively activated (M2) human macrophages on human dermal fibroblasts (HDFs).ResultsHDFs stimulated with paracrine factors from M1 macrophages showed a 10 to > 100-fold increase in the expression of the inflammatory cytokines IL6, CCL2 and CCL7 and the matrix metalloproteinases MMP1 and MMP3. This indicates that factors produced by M1 macrophages induce a fibroblast phenotype with pro-inflammatory and extracellular matrix (ECM) degrading properties. HDFs stimulated with paracrine factors secreted by M2 macrophages displayed an increased proliferation rate. Interestingly, the M1-activated pro-inflammatory fibroblasts downregulated, after exposure to paracrine factors produced by M2 macrophages or non-conditioned media, the inflammatory markers as well as MMPs and upregulated their collagen production.ConclusionsParacrine factors of M1 or M2 polarized macrophages induced different phenotypes of HDFs and the HDF phenotypes can in turn be reversed, pointing to a high dynamic plasticity of fibroblasts in the different phases of tissue repair.
Highlights
Macrophages and fibroblasts are two major players in tissue repair and fibrosis
Characterization of macrophages after Classically activated macrophages (M1) or Alternatively activated macrophages (M2) polarization Primary human macrophages responded to LPS/Interferon gamma (IFNG) or interleukin 4 (IL4)/IL13, resulting in M1 or M2 polarization, respectively
Macrophages stimulated for 48 h with LPS/IFNG showed an upregulation of the inflammatory genes interleukin 1 beta (IL1B), interleukin 6 (IL6) and CCL2 compared to M2 polarized and unstimulated macrophages (Figure 1C)
Summary
Macrophages and fibroblasts are two major players in tissue repair and fibrosis. In wound healing and fibrosis, a variety of processes are crucial, such as inflammation, cell proliferation, cell migration and extracellular matrix (ECM) remodeling. Two major cellular players in these processes are macrophages and fibroblasts [1,2,3,4]. During the proliferation phase of wound healing, fibroblasts proliferate and migrate into the wound site to form granulation tissue. Part of these fibroblasts differentiate into myofibroblasts and produce new ECM, mainly in the form of collagen, which is necessary to support cellular ingrowth. The degradation of collagen in the wound is mainly controlled by matrix metalloproteinases (MMPs).
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