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: Pam₃CSK₄ (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 Pam₃CSK₄-exposed HSPCs generate macrophages with a diminished ability to produce inflammatory cytokines. Interestingly, the Pam₃CSK₄-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).

中文翻译：

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从祖细胞体外巨噬细胞分化过程中的PRR信号调节其对炎症刺激的后续反应。

Toll样受体（TLR）激动剂驱使造血干细胞和祖细胞（HSPC）在体外以及感染后在体内沿骨髓谱系分化。在这项研究中，我们使用了HSPC分化的体外模型来研究将HSPC暴露于各种病原体相关分子模式（PAMP）和白色念珠菌对随后衍生的巨噬细胞具有的功能性后果（细胞因子产生）。在有或没有以下模式识别受体（PRR）激动剂的情况下，将小鼠HSPC（Lin ^–细胞）与GM-CSF培养以诱导巨噬细胞分化：Pam ₃ CSK ₄（TLR2配体），LPS（TLR4配体），耗尽的酵母聚糖（仅激活Dectin-1）或灭活的白色念珠菌酵母（其激活几种PRR，主要是TLR2和Dectin-1）。我们的数据表明，仅纯TLR2配体暴露（短暂和连续）会影响GM-CSF衍生的巨噬细胞的炎性功能，因为暴露于Pam ₃ CSK _4的HSPC会生成巨噬细胞，而其产生炎性细胞因子的能力降低。有趣的是，Pam ₃ CSK ₄诱导的巨噬细胞耐受性（通过瞬时暴露的HSPC）通过随后暴露于白色念珠菌而得到增强GM-CSF衍生的巨噬细胞中的细胞；然而，诱导的耐受性在M-CSF衍生的巨噬细胞中被部分逆转。因此，巨噬细胞产生炎性细胞因子的能力在很大程度上取决于其来源的HSPC如何接收和整合多种微环境信号（PRR配体和/或CSF）。