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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.This Review considers how the biophysical properties of a tissue are able to shape immune cell function through the process of mechanotransduction. There are multiple mechanotransduction pathways that operate in immune cells and the authors highlight these and the emerging field of mechanoimmunology.

Biomaterial wound dressings, such as hydrogels, interact with host cells to regulate tissue repair. This study investigates how crosslinking of gelatin-based hydrogels influences immune and stromal cell behavior and wound healing in female mice. We observe that softer, lightly crosslinked hydrogels promote greater cellular infiltration and result in smaller scars compared to stiffer, heavily crosslinked hydrogels. Using single-cell RNA sequencing, we further show that heavily crosslinked hydrogels increase inflammation and lead to the formation of a distinct macrophage subpopulation exhibiting signs of oxidative activity and cell fusion. Conversely, lightly crosslinked hydrogels are more readily taken up by macrophages and integrated within the tissue. The physical properties differentially affect macrophage and fibroblast interactions, with heavily crosslinked hydrogels promoting pro-fibrotic fibroblast activity that drives macrophage fusion through RANKL signaling. These findings suggest that tuning the physical properties of hydrogels can guide cellular responses and improve healing, offering insights for designing better biomaterials for wound treatment. Impaired wound healing that leads to scar remains a clinical challenge. Here, the authors study the effects of hydrogel crosslinking on cellular behavior in skin wounds and its effect on immune and stromal cell activity.

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. Clearance of apoptotic neutrophils by macrophages is important for the resolution of inflammation. Here, the authors show that interferon-β produced by resolution phase macrophages promotes neutrophil apoptosis and efferocytosis and induces macrophage reprogramming to a pro-resolving phenotype, thereby identifying IFN-β as a multi-pronged pro-resolution cytokine.

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 F4/80 and Ly6C F4/80 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 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.

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 β (IFN-β) was recently shown to facilitate macrophage reprogramming and resolution of inflammation. In this study, we found Gal-1null 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 12/15-lipoxygenase in macrophages and heightened levels of the inflammatory protease proteinase-3 (PR3) in peritoneal fluids from Gal-1null mice. Moreover, we observed sex-dependent differences in the inflammatory profile of Gal-1null mice. Notably, we found that IFN-β levels were reduced in resolution-phase exudates from Gal-1null mice. Administration of IFN-β in vivo or ex vivo treatment was able to rescue, at least in part, the hyperinflammatory profile of Gal-1null mice. In particular, IFN-β 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-1null mice. In conclusion, our results revealed a new Gal-1-IFN-β axis that facilitates the resolution of inflammation and might restrain uncontrolled inflammatory disorders.

[This corrects the article DOI: 10.3389/fimmu.2020.00405.].[This corrects the article DOI: 10.3389/fimmu.2020.00405.].

The resolution of inflammation is a central event in maintaining human health following infection and trauma, and deficiencies in its execution can lead to autoimmune and inflammatory disorders. The resolution of inflammation is hallmarked by programmed cell death (apoptosis) of the main infiltrating inflammatory cells - the neutrophils. Neutrophil corpse removal by macrophages, through a process termed efferocytosis, is critical for limiting inflammation, promoting wound repair, and avoiding tissue fibrosis. In addition to the clearance of self-antigens, efferocytosis results in macrophage reprogramming of cytokine production to anti-inflammatory phenotypes and immune-silencing. Here, we have characterized the dynamics of various myeloid subpopulations in spontaneously-resolving zymosan A-induced murine peritonitis, with a specific focus on a distinct population of resolution-promoting macrophages. These cells convert from pro-inflammatory and profibrotic precursors towards an anti-inflammatory/pro-resolving phenotype. These proresolving macrophages, characterized by low expression of CD11b and loss of phagocytic capacity (efferocytic satiation), were found to be central producers of the effector cytokine Interferon (IFN)-β, which in turn activates regulatory circuits to limit inflammation and promotes its resolution. During the resolution of inflammation, infiltrating inflammatory monocytes differentiate into reparative phagocytic macrophages. However, if not controlled in a timely fashion, these macrophages can also promote aberrant extracellular matrix deposition resulting in tissue fibrosis and scarring. Using a bleomycin-induced skin fibrosis model, we have found that the atypical chemokine receptor (ACKR2) is critical for limiting skin inflammation short of fibrotic scarring by reducing the levels of pro-inflammatory chemokines and pro-fibrotic cytokines. ACKR2- deficient mice presented exaggerated fibrotic indices accompanied by reduced levels of IFN- in comparison to their wild-type counterparts. Interestingly, subcutaneous treatment of skin lesions with IFN-β rescued most of the fibrotic parameters in ACKR2 deficient mice. Moreover, IFN--deficient mice also displayed enhanced fibrotic indices, albeit to a lower extent than their ACKR2-/- counterparts, suggesting IFN- is an essential pro-resolving cytokine in limiting inflammatory skin fibrosis. In addition, we uncover the role of the intracellular adaptor protein stimulator of IFN genes (STING) in the production of IFN-β by resolution-phase macrophages and consequently an essential role in promoting resolution-associated events. We show that satiated macrophages display increases in the activation of STING and its downstream signal transduction and STINGdeficient mice show reduced pro-resolving outcomes, including IFN- production, leukocyte kinetics, and macrophage efferocytosis ex vivo and reprogramming. We also found that the uptake of apoptotic cells in vivo and in vitro leads to leakage of double-stranded DNA fragments from phagolysosomes to the cytosol and association of the channel-forming protein Bax with these organelles. This phenomenon is the likely mechanism behind the activation of STING and the production of IFN-β during the resolution of inflammation. Altogether, this study establishes the importance of the STING-IFN- axis in macrophagemediated resolution of inflammation and prevention of skin fibrosis and can lead to novel therapeutic approaches towards autoimmune, inflammatory, and fibrotic disorders that involve STING activation or IFN- application.

  \"After the parliament passes a law on amnesty for those people who have been detained in the course of these actions, including radicals on condition that they didn't commit serious crimes, all of them will be freed,\" President Viktor Yanukovych said at a meeting with religious leaders. Opposition leader Vitali Klitschko, a former boxing champion, said proposals aired by Yanukovych Friday did not go far enough, calling them \"minimal steps\" and saying \"they cannot solve the crisis.\" \"I don't believe the negotiations will deliver any worthwhile results,\" Vladimir Bondarenko, a 28-year-old factory worker from the Lviv region, said in an interview with Tribune Newspapers. \"Yanukovych can't be trusted.\" Butenko, a special correspondent, reported from Kiev.

KIEV, Ukraine -- Security details and special police with the government of Ukraine's then-President Viktor Yanukovych were responsible for the deaths of protesters shot in February, officials with the nation's interim leadership said Thursday.

[...]even as the new president spoke of peace and economic reform, mortar fire struck a power station near the town of Slovyansk, the epicenter of the fighting, forcing the evacuation of technical personnel and cutting off electricity to part of the community and about 40 others in the surrounding district, the Unian news agency reported.