Martínez Alba, Bono Cristina, Megías Javier, Yáñez Alberto, Gozalbo Daniel, Gil M Luisa
Departamento de Microbiología y Ecología, Universitat de València, Burjassot, Spain, Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Burjassot, Spain.
Departamento de Patología, Universitat de València, Valencia, Spain.
Eur Cytokine Netw. 2017 Sep 1;28(3):102-110. doi: 10.1684/ecn.2017.0398.
Toll-like receptor (TLR) agonists drive hematopoietic stem and progenitor cells (HSPCs) to differentiate along the myeloid lineage in vitro and also in vivo following infection. In this study, we used an in vitro model of HSPC differentiation to investigate the functional consequences (cytokine production) that exposing HSPCs to various pathogen-associated molecular patterns (PAMPs) and Candida albicans cells have on the subsequently derived macrophages. Mouse HSPCs (Lin cells) were cultured with GM-CSF to induce macrophage differentiation in the presence or absence of the following pattern recognition receptor (PRR) agonists: PamCSK (TLR2 ligand), LPS (TLR4 ligand), depleted zymosan (which only activates Dectin-1), or inactivated C. albicans yeasts (which activate several PRRs, mainly TLR2 and Dectin-1). Our data show that only pure TLR2 ligand exposure (transient and continuous) impacts the inflammatory function of GM-CSF-derived macrophages, because PamCSK-exposed HSPCs generate macrophages with a diminished ability to produce inflammatory cytokines. Interestingly, the PamCSK-induced tolerance of macrophages (by transient exposure of HSPCs) is reinforced by subsequent exposure to C. albicans cells in GM-CSF-derived macrophages; however, the induced tolerance is partially reversed in M-CSF-derived macrophages. Therefore, the ability of macrophages to produce inflammatory cytokines is extremely dependent on how the HSPCs from which they are derived receive and integrate multiple microenvironmental signals (PRR ligands and/or CSFs).
Toll样受体（TLR）激动剂可驱动造血干细胞和祖细胞（HSPCs）在体外以及感染后的体内沿髓系谱系分化。在本研究中，我们使用HSPC分化的体外模型来研究将HSPCs暴露于各种病原体相关分子模式（PAMPs）和白色念珠菌细胞对随后产生的巨噬细胞的功能影响（细胞因子产生）。将小鼠HSPCs（Lin细胞）与GM-CSF一起培养，以在存在或不存在以下模式识别受体（PRR）激动剂的情况下诱导巨噬细胞分化：PamCSK（TLR2配体）、LPS（TLR4配体）、去聚糖酵母聚糖（仅激活Dectin-1）或热灭活的白色念珠菌酵母（激活多种PRR，主要是TLR2和Dectin-1）。我们的数据表明，只有单纯暴露于TLR2配体（短暂和持续）会影响GM-CSF衍生巨噬细胞的炎症功能，因为暴露于PamCSK的HSPCs产生的巨噬细胞产生炎性细胞因子的能力减弱。有趣的是，PamCSK诱导的巨噬细胞耐受性（通过HSPCs的短暂暴露）在GM-CSF衍生的巨噬细胞中随后暴露于白色念珠菌细胞时会增强；然而，在M-CSF衍生的巨噬细胞中，诱导的耐受性会部分逆转。因此，巨噬细胞产生炎性细胞因子的能力极大地取决于它们所源自的HSPCs接收和整合多种微环境信号（PRR配体和/或CSF）的方式。
