Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
Sci Transl Med. 2022 Jun 29;14(651):eabg7504. doi: 10.1126/scitranslmed.abg7504.
The role of tissue-resident macrophages during tissue regeneration or fibrosis is not well understood, mainly due to the lack of a specific marker for their identification. Here, we identified three populations of skeletal muscle-resident myelomonocytic cells: a population of macrophages positive for lymphatic vessel endothelial receptor 1 (LYVE1) and T cell membrane protein 4 (TIM4 or TIMD4), a population of LYVE1TIM4 macrophages, and a population of cells likely representing dendritic cells that were positive for CD11C and major histocompatibility complex class II (MHCII). Using a combination of parabiosis and lineage-tracing experiments, we found that, at steady state, TIM4 macrophages were replenished from the blood, whereas TIM4 macrophages locally self-renewed [self-renewing resident macrophages (SRRMs)]. We further showed that could be reliably used to distinguish SRRMs from damage-induced infiltrating macrophages. Using a colony-stimulating factor 1 receptor (CSF1R) inhibition/withdrawal approach to specifically deplete SRRMs, we found that SRRMs provided a nonredundant function in clearing damage-induced apoptotic cells early after extensive acute injury. In contrast, in chronic mild injury as seen in a mouse model of Duchenne muscular dystrophy, depletion of both TIM4- and TIM4-resident macrophage populations through long-term CSF1R inhibition changed muscle fiber composition from damage-sensitive glycolytic fibers toward damage-resistant glycolytic-oxidative fibers, thereby protecting muscle against contraction-induced injury both ex vivo and in vivo. This work reveals a previously unidentified role for resident macrophages in modulating tissue metabolism and may have therapeutic potential given the ongoing clinical testing of CSF1R inhibitors.
组织驻留巨噬细胞在组织再生或纤维化过程中的作用尚不清楚，主要是因为缺乏用于鉴定其的特异性标志物。在这里，我们鉴定了骨骼肌驻留髓系细胞的三个群体：一群表达淋巴管内皮受体 1（LYVE1）和 T 细胞膜蛋白 4（TIM4 或 TIMD4）的巨噬细胞，一群 LYVE1TIM4 巨噬细胞，以及一群可能代表树突状细胞的细胞，这些细胞对 CD11C 和主要组织相容性复合体 II（MHCII）呈阳性。通过联体动物和谱系追踪实验的组合，我们发现，在稳态下，TIM4 巨噬细胞来自血液补充，而 TIM4 巨噬细胞在局部自我更新[自我更新驻留巨噬细胞（SRRMs）]。我们进一步表明 可以可靠地用于区分 SRRMs 和损伤诱导的浸润巨噬细胞。使用集落刺激因子 1 受体（CSF1R）抑制/撤回方法特异性耗尽 SRRMs，我们发现 SRRMs 在广泛急性损伤后早期清除损伤诱导的凋亡细胞方面提供了非冗余功能。相比之下，在慢性轻度损伤中，如在杜氏肌营养不良症的小鼠模型中所见，通过长期 CSF1R 抑制耗尽 TIM4 和 TIM4 驻留巨噬细胞群体会改变肌肉纤维组成，从对损伤敏感的糖酵解纤维向对损伤有抵抗力的糖酵解-氧化纤维转变，从而在体外和体内保护肌肉免受收缩诱导的损伤。这项工作揭示了驻留巨噬细胞在调节组织代谢中的一个先前未被识别的作用，鉴于 CSF1R 抑制剂的临床测试正在进行中，这可能具有治疗潜力。
