CSF1R Dependent Genes.

Adaptation to existence outside the womb is a key event in the life of a mammal. The absence of macrophages in rats with a homozygous mutation in the colony-stimulating factor 1 receptor (Csf1r) gene (Csf1rko) severely compromises pre-weaning somatic growth and maturation of organ function. Transfer of wild-type bone marrow cells (BMT) at weaning rescues tissue macrophage populations permitting normal development and long-term survival. To dissect the phenotype and function of macrophages in postnatal development, we generated transcriptomic profiles of all major organs of wild-type and Csf1rko rats at weaning and in selected organs following rescue by BMT. The transcriptomic profiles revealed subtle effects of macrophage deficiency on development of all major organs. Network analysis revealed a common signature of CSF1R-dependent resident tissue macrophages that includes the components of complement C1Q (C1qa/b/c genes). Circulating C1Q was almost undetectable in Csf1rko rats and rapidly restored to normal levels following BMT. Tissue-specific macrophage signatures were also identified, notably including sinus macrophage populations in the lymph nodes. Their loss in Csf1rko rats was confirmed by immunohistochemical localisation of CD209B (SIGNR1). By 6-12 weeks, Csf1rko rats succumb to emphysema-like pathology associated with the selective loss of interstitial macrophages and granulocytosis. This pathology was reversed by BMT. Along with physiological rescue, BMT precisely regenerated the abundance and expression profiles of resident macrophages. The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia. In addition, the transferred BM failed to restore blood monocyte or CSF1R-positive bone marrow progenitors. These studies provide a model for the pathology and treatment of CSF1R mutations in humans and the innate immune deficiency associated with prematurity.

哺乳动物出生后适应宫外生存，是其生命历程中的关键事件。集落刺激因子1受体（colony-stimulating factor 1 receptor, Csf1r）基因纯合突变大鼠（Csf1rko）若缺失巨噬细胞，会严重损害其断奶前的躯体生长与器官功能成熟。于断奶时实施野生型骨髓细胞移植（bone marrow transplantation, BMT）可挽救组织巨噬细胞群，使其恢复正常发育并实现长期存活。为剖析巨噬细胞在出生后发育过程中的表型与功能，我们获取了断奶阶段野生型与Csf1rko大鼠全部主要器官，以及经BMT挽救后选定器官的转录组图谱。转录组图谱显示，巨噬细胞缺失对所有主要器官的发育仅存在细微影响。网络分析揭示了依赖CSF1R的组织驻留巨噬细胞存在共同特征，其包含补体C1Q（C1qa/b/c基因）的编码组分。Csf1rko大鼠体内几乎无法检测到循环C1Q，而经BMT移植后，其循环C1Q水平可快速恢复至正常范围。研究还鉴定出组织特异性巨噬细胞特征，其中尤以淋巴结内的窦巨噬细胞群最为突出。通过对CD209B（SIGNR1）进行免疫组织化学定位，证实了Csf1rko大鼠体内该细胞群的缺失。至6至12周龄时，Csf1rko大鼠会因间质巨噬细胞选择性缺失与粒细胞增多症，出现肺气肿样病理改变并最终死亡。该病理改变可通过BMT得到有效逆转。除实现生理功能挽救外，BMT还可精准重建驻留巨噬细胞的丰度与表达谱。唯一例外是脑部：骨髓来源的类小胶质细胞与驻留小胶质细胞的表达谱存在显著差异。此外，移植的骨髓无法重建血液单核细胞或CSF1R阳性骨髓祖细胞。本研究为人类CSF1R突变相关疾病的病理机制与治疗方案，以及早产相关先天免疫缺陷研究提供了理想的动物模型。