Departments of Biomedical Engineering and Chemical Engineering and Materials Science, and The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine, CA 92697.
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17253-8. doi: 10.1073/pnas.1308887110. Epub 2013 Oct 7.
Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Although much is known about how soluble factors influence macrophage polarization, relatively little is known about how physical cues present in the extracellular environment might modulate proinflammatory (M1) vs. prohealing (M2) activation. Specifically, the role of cell shape has not been explored, even though it has been observed that macrophages adopt different geometries in vivo. We and others observed that macrophages polarized toward different phenotypes in vitro exhibit dramatic changes in cell shape: M2 cells exhibit an elongated shape compared with M1 cells. Using a micropatterning approach to control macrophage cell shape directly, we demonstrate here that elongation itself, without exogenous cytokines, leads to the expression of M2 phenotype markers and reduces the secretion of inflammatory cytokines. Moreover, elongation enhances the effects of M2-inducing cytokines IL-4 and IL-13 and protects cells from M1-inducing stimuli LPS and IFN-γ. In addition shape- but not cytokine-induced polarization is abrogated when actin and actin/myosin contractility are inhibited by pharmacological agents, suggesting a role for the cytoskeleton in the control of macrophage polarization by cell geometry. Our studies demonstrate that alterations in cell shape associated with changes in ECM architecture may provide integral cues to modulate macrophage phenotype polarization.
巨噬细胞表型的极化受局部组织微环境中环境线索的调节。尽管人们已经了解了可溶性因子如何影响巨噬细胞极化，但对于细胞外环境中存在的物理线索如何调节促炎（M1）与促修复（M2）激活知之甚少。具体来说，尽管已经观察到巨噬细胞在体内采用不同的形态，但细胞形状的作用尚未得到探索。我们和其他人观察到，体外极化到不同表型的巨噬细胞在细胞形状上发生了显著变化：M2 细胞比 M1 细胞呈现出更长的形状。通过微图案化方法直接控制巨噬细胞的形状，我们在此证明，即使没有外源性细胞因子，细胞的伸长本身也会导致 M2 表型标志物的表达，并减少炎症细胞因子的分泌。此外，伸长增强了 M2 诱导细胞因子 IL-4 和 IL-13 的作用，并保护细胞免受 M1 诱导刺激 LPS 和 IFN-γ 的影响。此外，当肌动蛋白和肌动球蛋白收缩性被药物抑制时，形状而不是细胞因子诱导的极化被消除，这表明细胞骨架在细胞形状控制巨噬细胞极化中起作用。我们的研究表明，与细胞外基质结构变化相关的细胞形状改变可能为调节巨噬细胞表型极化提供重要线索。
