The uptake of apoptotic polymorphonuclear cells (PMN) by macrophages is critical for timely resolution of inflammation. High-burden uptake of apoptotic cells is associated with loss of phagocytosis in resolution phase macrophages. Here, using a transcriptomic analysis of macrophage subsets, we show that non-phagocytic resolution phase macrophages express a distinct IFN-β-related gene signature in mice. We also report elevated levels of IFN-β in peritoneal and broncho-alveolar exudates in mice during the resolution of peritonitis and pneumonia, respectively. Elimination of endogenous IFN-β impairs, whereas treatment with exogenous IFN-β enhances, bacterial clearance, PMN apoptosis, efferocytosis and macrophage reprogramming. STAT3 signalling in response to IFN-β promotes apoptosis of human PMNs. Finally, uptake of apoptotic cells promotes loss of phagocytic capacity in macrophages alongside decreased surface expression of efferocytic receptors in vivo. Collectively, these results identify IFN-β produced by resolution phase macrophages as an effector cytokine in resolving bacterial inflammation.

Immune responses are governed by signals from the tissue microenvironment, and in addition to biochemical signals, mechanical cues and forces arising from the tissue, its extracellular matrix and its constituent cells shape immune cell function. Indeed, changes in biophysical properties of tissue alter the mechanical signals experienced by cells in many disease conditions, in inflammatory states and in the context of ageing. These mechanical cues are converted into biochemical signals through the process of mechanotransduction, and multiple pathways of mechanotransduction have been identified in immune cells. Such pathways impact important cellular functions including cell activation, cytokine production, metabolism, proliferation and trafficking. Changes in tissue mechanics may also represent a new form of ‘danger signal’ that alerts the innate and adaptive immune systems to the possibility of injury or infection. Tissue mechanics can change temporally during an infection or inflammatory response, offering a novel layer of dynamic immune regulation. Here, we review the emerging field of mechanoimmunology, focusing on how mechanical cues at the scale of the tissue environment regulate immune cell behaviours to initiate, propagate and resolve the immune response.

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 Ly6C med F4/80 − and Ly6C hi F4/80 lo 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 Ly6C lo macrophages and monocyte-derived macrophages more than their precursors, inflammatory Ly6C hi 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 Butenko et al. Non-Phagocytic Macrophages Express an Anti-Fibrotic Transcriptomewere 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.

During the resolution of acute inflammation, macrophages undergo reprogramming from pro-inflammatory, to anti-inflammatory/reparative, and eventually to pro-resolving macrophages. Galectin-1 (Gal-1) is a bona fide pro-resolving lectin while interferon b (IFN-b) was recently shown to facilitate macrophage reprogramming and resolution of inflammation. In this study, we found Gal-1 null mice exhibit a hyperinflammatory phenotype during the resolution of zymosan A-induced peritonitis but not during the early inflammatory response. This phenotype was characterized by reduced macrophage numbers, increased secretion of pro-inflammatory cytokines, such as interleukin-12 (IL-12), and reduced secretion of anti-inflammatory cytokines, such as interleukin-10 (IL-10). In addition, we found a delayed expression of the pro-resolving enzyme 12/15lipoxygenase in macrophages and heightened levels of the inflammatory protease proteinase-3 (PR3) in peritoneal fluids from Gal-1 null mice. Moreover, we observed sexdependent differences in the inflammatory profile of Gal-1 null mice. Notably, we found that IFN-b levels were reduced in resolution-phase exudates from Gal-1 null mice. Administration of IFN-b in vivo or ex vivo treatment was able to rescue, at least in part, the hyperinflammatory profile of Gal-1 null mice. In particular, IFN-b recovered a subset of F4/80 + GR-1 + macrophages, restored IL-12 and IL-10 secretion from macrophages to WT values and diminished abnormal peritoneal PR3 levels in Gal-1 null mice. In conclusion, our results revealed a new Gal-1-IFN-b axis that facilitates the resolution of inflammation and might restrain uncontrolled inflammatory disorders.

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Skin fibrosis is a deleterious outcome of a dysregulated and progressive healing phase of inflammation. 1,2 Resolution of inflammation is essential for proper wound healing and limits tissue repair short of exuberant fibrotic scarring. [3][4][5] During the resolution of inflammation, infiltrating inflammatory monocytes differentiate to reparative phagocytic macrophages. 6,7 However, if not controlled in a timely fashion, these macrophages can also promote tissue fibrosis. 8,9 Extracellular matrix (ECM) proteins, such as various collagen subtypes, fibronectin, laminin, and others, are produced during tissue repair and the resolution of inflammation mainly by fibroblasts that