Cell plasticity in wound healing: paracrine factors of M1/ M2 polarized macrophages influence the phenotypical state of dermal fibroblasts

TLDR

Macrophages and fibroblasts are key players in tissue repair and fibrosis, yet little is known about whether macrophages can influence fibroblast properties. The study examined how paracrine factors from classically (M1) and alternatively (M2) activated human macrophages affect human dermal fibroblasts. Human dermal fibroblasts were exposed to conditioned media from M1 or M2 macrophages, and expression of inflammatory cytokines, MMPs, proliferation, and collagen production was measured. M1-derived factors induced a pro‑inflammatory, ECM‑degrading fibroblast phenotype, whereas M2-derived factors promoted proliferation and, after exposure, reversed M1-induced inflammation and enhanced collagen production, demonstrating fibroblast plasticity.

Abstract

Macrophages 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).HDFs 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.Paracrine 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.