Department of Human Biology, University of Haifa, Haifa, Israel.
Tauber Bioinformatics Center, University of Haifa, Haifa, Israel.
Front Immunol. 2020 Mar 31;11:405. doi: 10.3389/fimmu.2020.00405. eCollection 2020.
Monocyte-derived macrophages are readily differentiating cells that adapt their gene expression profile to environmental cues and functional needs. During the resolution of inflammation, monocytes initially differentiate to reparative phagocytic macrophages and later to pro-resolving non-phagocytic macrophages that produce high levels of IFNβ to boost resolutive events. Here, we performed in-depth analysis of phagocytic and non-phagocytic myeloid cells to reveal their distinct features. Unexpectedly, our analysis revealed that the non-phagocytic compartment of resolution phase myeloid cells is composed of Ly6CF4/80 and Ly6CF4/80 monocytic cells in addition to the previously described Ly6CF4/80 satiated macrophages. In addition, we found that both Ly6C monocytic cells differentiate to Ly6CF4/80macrophages, and their migration to the peritoneum is CCR2 dependent. Notably, satiated macrophages expressed high levels of IFNβ, whereas non-phagocytic monocytes of either phenotype did not. A transcriptomic comparison of phagocytic and non-phagocytic resolution phase F4/80 macrophages showed that both subtypes express similar gene signatures that make them distinct from other myeloid cells. Moreover, we confirmed that these macrophages express closer transcriptomes to monocytes than to resident peritoneal macrophages (RPM) and resemble resolutive Ly6C macrophages and monocyte-derived macrophages more than their precursors, inflammatory Ly6C monocytes, recovered following liver injury and healing, and thioglycolate-induced peritonitis, respectively. A direct comparison of these subsets indicated that the non-phagocytic transcriptome is dominated by satiated macrophages and downregulate gene clusters associated with excessive tissue repair and fibrosis, ROS and NO synthesis, glycolysis, and blood vessel morphogenesis. On the other hand, non-phagocytic macrophages enhance the expression of genes associated with migration, oxidative phosphorylation, and mitochondrial fission as well as anti-viral responses when compared to phagocytic macrophages. Notably, conversion from phagocytic to satiated macrophages is associated with a reduction in the expression of extracellular matrix constituents that were demonstrated to be associated with idiopathic pulmonary fibrosis (IPF). Thus, macrophage satiation during the resolution of inflammation seems to bring about a transcriptomic transition that resists tissue fibrosis and oxidative damage while promoting the restoration of tissue homeostasis to complete the resolution of inflammation.
单核细胞衍生的巨噬细胞是易于分化的细胞，能够根据环境线索和功能需求调整其基因表达谱。在炎症消退过程中，单核细胞最初分化为修复性吞噬巨噬细胞，然后分化为产生高水平 IFNβ以促进消退事件的促消退非吞噬巨噬细胞。在这里，我们对吞噬性和非吞噬性髓样细胞进行了深入分析，以揭示它们的独特特征。出乎意料的是，我们的分析表明，炎症消退阶段髓样细胞的非吞噬细胞区室除了先前描述的饱食 Ly6CF4/80 巨噬细胞外，还由 Ly6CF4/80 和 Ly6CFO/80 单核细胞组成。此外，我们发现 Ly6C 单核细胞均分化为 Ly6CF4/80 巨噬细胞，它们向腹膜的迁移依赖于 CCR2。值得注意的是，饱食巨噬细胞表达高水平的 IFNβ，而无论表型如何，非吞噬性单核细胞均不表达。吞噬性和非吞噬性消退阶段 F4/80 巨噬细胞的转录组比较表明，这两种亚型均表达相似的基因特征，使它们有别于其他髓样细胞。此外，我们证实这些巨噬细胞的转录组与单核细胞更相似，而与驻留性腹膜巨噬细胞（RPM）和类似于消退 Ly6C 巨噬细胞和单核细胞衍生的巨噬细胞更相似，而不是其前体，炎症性 Ly6C 单核细胞，分别在肝损伤和愈合以及巯基乙醇酸盐诱导的腹膜炎后恢复。对这些亚群的直接比较表明，非吞噬性转录组主要由饱食巨噬细胞组成，并下调与过度组织修复和纤维化、ROS 和 NO 合成、糖酵解和血管形态发生相关的基因簇。另一方面，与吞噬性巨噬细胞相比，非吞噬性巨噬细胞增强了与迁移、氧化磷酸化和线粒体裂变以及抗病毒反应相关的基因的表达。值得注意的是，从吞噬性到饱食性巨噬细胞的转化与细胞外基质成分的表达减少相关，这些成分与特发性肺纤维化（IPF）有关。因此，在炎症消退过程中巨噬细胞的饱食似乎会引起转录组的转变，从而抵抗组织纤维化和氧化损伤，同时促进组织内稳态的恢复，以完成炎症的消退。
