Abstract
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 Ly6CmedF4/80− and Ly6ChiF4/80lo monocytic cells in addition to the previously described Ly6C−F4/80+ satiated macrophages. In addition, we found that both Ly6C+ monocytic cells differentiate to Ly6C−F4/80+macrophages, 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 Ly6Clo macrophages and monocyte-derived macrophages more than their precursors, inflammatory Ly6Chi 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.
Highlights
Acute inflammation is the protective response of the host to damaging events that may interrupt tissue homeostasis, such as physical or chemical injury, as well as microbial infections
This conversion is associated with a transition of a F4/80−PKH2lo monocyte subset to an F4/80+PKH2hi macrophage subset reflecting improved phagocytosis upon maturation
Notable is the presence of a small Ly6ChiF4/80lo subset, commonly regarded as classical inflammatory monocytes, that is sustained during resolution but does not acquire phagocytic capacity and remains PKH2neg (Figure 1C)
Summary
Acute inflammation is the protective response of the host to damaging events that may interrupt tissue homeostasis, such as physical or chemical injury, as well as microbial infections. Upon the arrival of these leukocytes, mostly neutrophils, they primarily function to phagocytose and eliminate foreign microorganisms via distinct intracellular killing mechanisms, resulting in neutrophils undergoing programmed cell death (apoptosis) [1, 2]. This occurs alongside monocyte influx and their maturation into inflammatory macrophages upon infiltration of the inflamed tissue. Inflammatory macrophages polarize to distinct subpopulations following exposure to different bioactive molecules and environments These subpopulations compose a wide spectrum of phenotypes that range from classically (M1) to alternatively (M2) activated macrophages—two commonly used myeloid measuring sticks generated during responses to bacterial or helminth infections and support Th1 or Th2 development, respectively [6]. The current literature promotes the usage of marker combinations or inducing agents to ascribe macrophage phenotypes rather than the M1 and M2 extremes [6, 10, 11]
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