Engineering Immunomodulatory Biomaterials to Drive Skin Wounds toward Regenerative Healing.

The healing of human skin wounds is designed for a rapid fibroproliferative response at the expense of tissue complexity and is therefore prone to scar formation. Moreover, wound healing often goes awry when excessive inflammation leads to chronic nonhealing wounds or when excessive repair results in uncontrolled tissue fibrosis. The immune system plays a central role in orchestrating wound healing, and, thus, controlling immune cell activities holds great potential for reducing scars and enhancing regeneration. Biomaterial dressings directly interact with immune cells in the wound and have been shown to improve the repair process. A few studies have even shown that biomaterials can induce complete regeneration through mechanisms involving immune cells. Here, we review the role of the immune system in skin repair and regeneration and describe how advances in biomaterial research may uncover immunomodulatory elements to enhance fully functional skin regeneration.

Tuning immunity through tissue mechanotransduction.

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.

ACKR2 limits skin fibrosis and hair loss through IFN-ß.

The resolution of inflammation facilitates proper wound healing and limits tissue repair short of exaggerated fibrotic scarring. The atypical chemokine receptor (ACKR)2/D6 scavenges inflammatory chemokines, while IFN-ß is a recently unveiled pro-resolving cytokine. Both effector molecules limit acute inflammatory episodes and promote their resolution in various organs. Here, we found fibrotic skin lesions from ACKR2-/- mice presented increased epidermal and dermal thickening, atrophy of the subcutaneous adipose tissue, augmented disorientation of collagen deposition, and enhanced deformation and loss of hair follicles compared to WT counterparts. In addition, affected skin sections from ACKR2-/- mice contained reduced levels of the pro-resolving mediators IFN-ß and IL-10, but increased levels of the pro-inflammatory chemokines CCL2 and 3, the pro-fibrotic cytokine TGF-ß, and the immune-stimulating cytokine IL-12. Notably, treatment with exogenous IFN-ß rescued, at least in part, all the pro-fibrotic outcomes and lesion size in ACKR2-/- mice and promoted expression of the pro-resolving enzyme 12/15-lipoxygenase (LO) in both ACKR2-/- and WT mice. Moreover, Ifnb-/- mice displayed enhanced pro-fibrotic indices upon exposure to bleomycin. These findings suggest ACKR2 is an important mediator in limiting inflammatory skin fibrosis and acts via IFN-ß production to promote the resolution of inflammation and minimize tissue scaring.

Galectin-1 Facilitates Macrophage Reprogramming and Resolution of Inflammation Through IFN-ß.

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 ß (IFN-ß) 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-ß levels were reduced in resolution-phase exudates from Gal-1null mice. Administration of IFN-ß in vivo or ex vivo treatment was able to rescue, at least in part, the hyperinflammatory profile of Gal-1null mice. In particular, IFN-ß 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-ß axis that facilitates the resolution of inflammation and might restrain uncontrolled inflammatory disorders.

Corrigendum: Transcriptomic Analysis of Monocyte-Derived Non-Phagocytic Macrophages Favors a Role in Limiting Tissue Repair and Fibrosis.

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

Transcriptomic Analysis of Monocyte-Derived Non-Phagocytic Macrophages Favors a Role in Limiting Tissue Repair and Fibrosis.

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 IFNß 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 IFNß, 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.

IFN-ß is a macrophage-derived effector cytokine facilitating the resolution of bacterial inflammation.

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-ß-related gene signature in mice. We also report elevated levels of IFN-ß in peritoneal and broncho-alveolar exudates in mice during the resolution of peritonitis and pneumonia, respectively. Elimination of endogenous IFN-ß impairs, whereas treatment with exogenous IFN-ß enhances, bacterial clearance, PMN apoptosis, efferocytosis and macrophage reprogramming. STAT3 signalling in response to IFN-ß 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-ß produced by resolution phase macrophages as an effector cytokine in resolving bacterial inflammation.