School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia.
Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia.
J Cell Sci. 2020 Mar 2;133(5):jcs232405. doi: 10.1242/jcs.232405.
Migratory macrophages play critical roles in tissue development, homeostasis and disease, so it is important to understand how their migration machinery is regulated. Whole-transcriptome sequencing revealed that CSF-1-stimulated differentiation of bone marrow-derived precursors into mature macrophages is accompanied by widespread, profound changes in the expression of genes regulating adhesion, actin cytoskeletal remodeling and extracellular matrix degradation. Significantly altered expression of almost 40% of adhesion genes, 60-86% of Rho family GTPases, their regulators and effectors and over 70% of extracellular proteases occurred. The gene expression changes were mirrored by changes in macrophage adhesion associated with increases in motility and matrix-degrading capacity. IL-4 further increased motility and matrix-degrading capacity in mature macrophages, with additional changes in migration machinery gene expression. Finally, siRNA-induced reductions in the expression of the core adhesion proteins paxillin and leupaxin decreased macrophage spreading and the number of adhesions, with distinct effects on adhesion and their distribution, and on matrix degradation. Together, the datasets provide an important resource to increase our understanding of the regulation of migration in macrophages and to develop therapies targeting disease-enhancing macrophages.
游走巨噬细胞在组织发育、稳态和疾病中发挥着关键作用，因此了解它们的迁移机制如何被调控非常重要。全转录组测序显示，CSF-1 刺激骨髓来源前体分化为成熟巨噬细胞的过程中，调控黏附、肌动蛋白细胞骨架重塑和细胞外基质降解的基因表达发生广泛而深刻的变化。近 40%的黏附基因、60-86%的Rho 家族 GTPases 及其调节剂和效应物以及超过 70%的细胞外蛋白酶的表达发生了显著改变。基因表达的变化反映在与运动性和基质降解能力增加相关的巨噬细胞黏附的变化上。IL-4 进一步增加了成熟巨噬细胞的运动性和基质降解能力，同时迁移机制基因表达也发生了额外的变化。最后，siRNA 诱导的核心黏附蛋白 paxillin 和 leupaxin 的表达减少，导致巨噬细胞铺展和黏附数量减少，对黏附和它们的分布以及基质降解有明显的影响。总的来说，这些数据集为增加我们对巨噬细胞迁移调控的理解提供了一个重要的资源，并为靶向疾病增强型巨噬细胞的治疗方法的开发提供了依据。
