Ordaz-Arias Manuel Azaid, Díaz-Alvarez Laura, Zúñiga Joaquín, Martinez-Sánchez Mariana Esther, Balderas-Martínez Yalbi Itzel
Laboratorio de Biopatología Pulmonar, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
Licenciatura en Ciencias Genómicas, UNAM, Cuernavaca, Mexico.
Front Mol Biosci. 2022 Apr 11;9:807228. doi: 10.3389/fmolb.2022.807228. eCollection 2022.
Adaptability, heterogeneity, and plasticity are the hallmarks of macrophages. How these complex properties emerge from the molecular interactions is an open question. Thus, in this study we propose an actualized regulatory network of cytokines, signaling pathways, and transcription factors to survey the differentiation, heterogeneity, and plasticity of macrophages. The network recovers attractors, which in regulatory networks correspond to cell types, that correspond to M0, M1, M2a, M2b, M2c, M2d, M2-like, and IL-6 producing cells, including multiple cyclic attractors that are stable to perturbations. These cyclic attractors reproduce experimental observations and show that oscillations result from the structure of the network. We also study the effect of the environment in the differentiation and plasticity of macrophages, showing that the observed heterogeneity in macrophage populations is a result of the regulatory network and its interaction with the micro-environment. The macrophage regulatory network gives a mechanistic explanation to the heterogeneity and plasticity of macrophages seen and , and offers insights into the mechanism that allows the immune system to react to a complex dynamic environment.
适应性、异质性和可塑性是巨噬细胞的标志。这些复杂特性如何从分子相互作用中产生仍是一个悬而未决的问题。因此，在本研究中，我们提出了一个由细胞因子、信号通路和转录因子组成的实时调控网络，以研究巨噬细胞的分化、异质性和可塑性。该网络恢复了吸引子，在调控网络中，吸引子对应于细胞类型，分别对应于M0、M1、M2a、M2b、M2c、M2d、M2样细胞以及产生IL-6的细胞，包括多个对扰动稳定的循环吸引子。这些循环吸引子再现了实验观察结果，并表明振荡是由网络结构引起的。我们还研究了环境对巨噬细胞分化和可塑性的影响，结果表明，在巨噬细胞群体中观察到的异质性是调控网络及其与微环境相互作用的结果。巨噬细胞调控网络为所观察到的巨噬细胞异质性和可塑性提供了一个机制性解释，并为免疫系统对复杂动态环境作出反应的机制提供了见解。
