Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
PLoS Comput Biol. 2022 Oct 3;18(10):e1010092. doi: 10.1371/journal.pcbi.1010092. eCollection 2022 Oct.
Phagocytosis, the biological process in which cells ingest large particles such as bacteria, is a key component of the innate immune response. Fcγ receptor (FcγR)-mediated phagocytosis is initiated when these receptors are activated after binding immunoglobulin G (IgG). Receptor activation initiates a signaling cascade that leads to the formation of the phagocytic cup and culminates with ingestion of the foreign particle. In the experimental system termed "frustrated phagocytosis", cells attempt to internalize micropatterned disks of IgG. Cells that engage in frustrated phagocytosis form "rosettes" of actin-enriched structures called podosomes around the IgG disk. The mechanism that generates the rosette pattern is unknown. We present data that supports the involvement of Cdc42, a member of the Rho family of GTPases, in pattern formation. Cdc42 acts downstream of receptor activation, upstream of actin polymerization, and is known to play a role in polarity establishment. Reaction-diffusion models for GTPase spatiotemporal dynamics exist. We demonstrate how the addition of negative feedback and minor changes to these models can generate the experimentally observed rosette pattern of podosomes. We show that this pattern formation can occur through two general mechanisms. In the first mechanism, an intermediate species forms a ring of high activity around the IgG disk, which then promotes rosette organization. The second mechanism does not require initial ring formation but relies on spatial gradients of intermediate chemical species that are selectively activated over the IgG patch. Finally, we analyze the models to suggest experiments to test their validity.
吞噬作用是细胞摄取细菌等大颗粒的生物学过程，是先天免疫反应的关键组成部分。Fcγ 受体（FcγR）介导的吞噬作用是在这些受体与免疫球蛋白 G（IgG）结合后被激活时启动的。受体的激活引发信号级联反应，导致吞噬杯的形成，并最终吞噬外来颗粒。在称为“受挫吞噬”的实验系统中，细胞试图内化 IgG 微图案化的圆盘。参与受挫吞噬的细胞在 IgG 盘周围形成富含肌动蛋白的结构的“玫瑰花结”，称为 Podosomes。产生玫瑰花结模式的机制尚不清楚。我们提供的数据支持 Rho 家族 GTPase 成员 Cdc42 参与模式形成。Cdc42 在受体激活的下游，肌动蛋白聚合的上游起作用，并且已知在极性建立中起作用。存在 GTPase 时空动力学的反应扩散模型。我们展示了如何通过向这些模型添加负反馈和较小的更改来生成实验观察到的 Podosomes 的玫瑰花结模式。我们表明，这种模式形成可以通过两种一般机制发生。在第一种机制中，中间物质在 IgG 盘周围形成高活性环，然后促进玫瑰花结组织。第二种机制不需要初始环形成，但依赖于中间化学物质的空间梯度，这些化学物质选择性地在 IgG 斑块上被激活。最后，我们分析模型以提出实验来测试它们的有效性。
