c-MAF defines the phenotype of a family of perivascular macrophages

Tissue-resident Macrophages have long been appreciated as playing a fundamental role in the ontogeny and function of several organs. For example, osteoclasts are crucial for proper bone remodeling, microglia for synaptic pruning, and lung alveolar macrophages for clearance of surfactant. Perivascular macrophages have been described in many organs. Our analysis of murine perivascular macrophages in several tissues and organs led us to define a macrophage family, whose members share the expression of a number of surface molecules that are not typically considered macrophage markers, such as Lyve1, Folate Receptor 2 (Folr2), Enpep/CD249, and CD38, as well as other more typical macrophage markers such as CD206 and Tim4. This family of perivascular macrophages also occurs in humans. Importantly, this family of perivascular macrophages relies on the transcription factor c-MAF, encoded by the gene Maf, for its full function. Conditional deletion of the Maf gene in the Lyve1+Folr2+CD38+ macrophage family caused their ablation in the brain, without impact on the microglia, while in the adipose tissue the conditional deletion of the Maf gene in perivascular macrophages resulted in a profoundly altered macrophage gene expression, and brought about an increased vascular branching in this tissue. Mice with conditional Maf deletion were protected from metabolic syndrome when submitted to high fat diet (HFD). Our results show that c-MAF is the master regulator of a family of perivascular macrophages. Examination of RNA expression changes in Perivascular macrophages from epididymal adipose tissue. Macrophages conditionallly ablated of CMAF expression were compared to WT counterparts组织驻留巨噬细胞（Tissue-resident Macrophages）长期以来被认为在多个器官的个体发生与功能中发挥基础性作用。例如，破骨细胞（osteoclasts）对正常骨重塑至关重要，小胶质细胞（microglia）负责突触修剪，而肺泡巨噬细胞（lung alveolar macrophages）则参与表面活性物质的清除。多种器官中均已报道存在血管周巨噬细胞（perivascular macrophages）。我们对多个组织与器官中的小鼠血管周巨噬细胞进行分析后，定义了一类巨噬细胞家族：该家族成员共同表达多种通常不被视为巨噬细胞标志物的表面分子，例如Lyve1、叶酸受体2（Folate Receptor 2, Folr2）、Enpep/CD249以及CD38，同时也表达CD206、Tim4等更为典型的巨噬细胞标志物。这类血管周巨噬细胞家族在人类体内同样存在。尤为重要的是，该家族的完整功能依赖于由基因Maf编码的转录因子c-MAF。在Lyve1+Folr2+CD38+巨噬细胞家族中条件性敲除Maf基因，会导致其在大脑中被清除，却不会影响小胶质细胞；而在脂肪组织中，对血管周巨噬细胞的Maf基因进行条件性敲除，会显著改变巨噬细胞的基因表达谱，并引发该组织内血管分支的增多。接受高脂饮食（high fat diet, HFD）的条件性Maf敲除小鼠，可免受代谢综合征的侵扰。我们的研究结果表明，c-MAF是一类血管周巨噬细胞家族的主调控因子。本研究检测了附睾脂肪组织血管周巨噬细胞的RNA表达变化，并将CMAF表达被条件性敲除的巨噬细胞与野生型（WT）对照样本进行了比较。