While neutrophil production in emergency states has been extensively studied, regulation of neutrophil homeostasis in the steady-state remained incompletely understood. We have shown that innate immune receptor toll-like receptor (TLR)4 and downstream TIR-domain-containing adapter-inducing interferon-β (TRIF) are indispensable for the generation of a granulocyte-colony stimulating factor (G-CSF)-dependent regulatory feedback loop upon antibody-induced neutropenia. These findings demonstrated that steady-state granulopoiesis is a demand-driven process, which may rely on differential triggering of innate immune receptors by microbial cell wall constituents such as lipopolysaccharide. Herein, we present further evidence on underlying mechanisms: oral intake of highly endotoxic lipopolysaccharide, but not TLR-antagonistic lipopolysaccharide derived from Rhodobacter sphaeroides, induces hematopoietic stem and progenitor cell fate decisions toward the neutrophil lineage independent of G-CSF. TLR4 has been identified as the indispensable sensor for oral lipopolysaccharide-modulated steady-state granulopoiesis. These results have important implications: food lipopolysaccharide content or the composition of the gastrointestinal microbiome may be strongly underrated as determinants of peripheral blood neutrophil levels. Both neutrophilia and neutropenia are associated with drastically worse outcomes in epidemiological studies of the general population as well as in diseased states.

Impact statement

In our present study, we investigated the impact of LPS on neutrophil homeostasis and found that oral intake is sufficient to induce hematopoietic stem and progenitor cell fate decisions towards the neutrophil lineage independent of G-CSF. In addition, TLR4 has been identified as the indispensable sensor for oral LPS-modulated steady-state granulopoiesis. We provide evidence that the gastrointestinal microbiome is critical for neutrophil homeostasis, which has implications for patients being treated with chemotherapy or antimicrobial therapy, since both are significantly influencing the composition of the intestinal microbiome.

中文翻译：

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口服脂多糖可调节 Toll 样受体 4 依赖性粒细胞生成。

虽然已经对紧急状态下的中性粒细胞产生进行了广泛的研究，但对稳态中中性粒细胞稳态的调节仍未完全了解。我们已经证明先天免疫受体 toll 样受体 (TLR)4 和下游含有 TIR 结构域的接头诱导干扰素-β (TRIF) 对于产生粒细胞集落刺激因子 (G-CSF) 依赖性是必不可少的抗体诱导的中性粒细胞减少的调节反馈回路。这些发现表明，稳态粒细胞生成是一个需求驱动的过程，这可能依赖于微生物细胞壁成分（如脂多糖）对先天免疫受体的差异触发。在此，我们提供了有关潜在机制的进一步证据：口服摄入高内毒脂多糖，Rhodobacter sphaeroide s，诱导造血干细胞和祖细胞对中性粒细胞谱系的命运决定，独立于 G-CSF。TLR4 已被确定为口服脂多糖调节稳态粒细胞生成不可或缺的传感器。这些结果具有重要意义：食物脂多糖含量或胃肠道微生物组的组成可能被严重低估作为外周血中性粒细胞水平的决定因素。中性粒细胞增多症和中性粒细胞减少症都与普通人群和患病状态的流行病学研究结果显着恶化有关。

影响陈述

在我们目前的研究中，我们研究了 LPS 对中性粒细胞稳态的影响，发现口服摄入足以诱导造血干细胞和祖细胞对中性粒细胞谱系的命运决定，而与 G-CSF 无关。此外，TLR4 已被确定为口服 LPS 调节稳态粒细胞生成不可或缺的传感器。我们提供证据表明胃肠道微生物组对中性粒细胞稳态至关重要，这对接受化疗或抗菌治疗的患者有影响，因为两者都显着影响肠道微生物组的组成。