Macrophages in Tissue Repair, Regeneration, and Fibrosis

The immune system plays a pivotal role in the initiation, development and resolution of inflammation following insult or damage to organs. The heart is a vital organ which supplies nutrients and oxygen to all parts of the body. Heart failure (HF) has been conventionally described as a disease associated with cardiac tissue damage caused by systemic inflammation, arrhythmia and conduction defects. Cardiac inflammation and subsequent tissue damage is orchestrated by the infiltration and activation of various immune cells including neutrophils, monocytes, macrophages, eosinophils, mast cells, natural killer cells, and T and B cells into the myocardium. After tissue injury, monocytes and tissue-resident macrophages undergo marked phenotypic and functional changes, and function as key regulators of tissue repair, regeneration and fibrosis. Disturbance in resident macrophage functions such as uncontrolled production of inflammatory cytokines, growth factors and inefficient generation of an anti-inflammatory response or unsuccessful communication between macrophages and epithelial and endothelial cells and fibroblasts can lead to aberrant repair, persistent injury, and HF. Therefore, in this review, we discuss the role of cardiac macrophages on cardiac inflammation, tissue repair, regeneration and fibrosis.

Achilles tendon rupture prognosis is usually unsatisfactory. After the tendon is injured, it may not function properly because of the fibrotic healing response, which restrains tendon motion. Inflammatory monocytes and tissue-resident macrophages are indispensable regulators in tissue repair, fibrosis, and regeneration. Exosomes from macrophages are crucial factors in tissue microenvironment regulation following tissue injury. This study therefore aimed to clarify the roles of macrophage exosomes in tendon injury (TI) repair. The results show that macrophages play a role after TI. M1 macrophages were increased relative to peritendinous fibrosis after TI. High-throughput sequencing showed abnormal expression of circular RNAs (circRNAs) between exosomes from M2 and M0 macrophages. Among the abnormal expressions of circRNA, circRNA-Ep400 was significantly increased in M2 macrophage exosomes. The results also show that M2 macrophage-derived circRNA-Ep400-containing exosomes are important for promoting peritendinous fibrosis after TI. Bioinformatics and dual-luciferase reporting experiments confirmed that miR-15b-5p and fibroblast growth factor (FGF)-1/7/9 were downstream targets of circRNA-Ep400. High circRNA-Ep400-containing exosome treatment inhibited miR-15b-5p, but promoted FGF1/7/9 expression in both fibroblasts and tenocytes. Furthermore, high circRNA-Ep400-containing exosome treatment promoted fibrosis, proliferation, and migration in both fibroblasts and tenocytes. Taken together, the results show that M2 macrophage-derived circRNA-Ep400-containing exosomes promote peritendinous fibrosis after TI via the miR-15b-5p/FGF-1/7/9 pathway, which suggests novel therapeutics for tendon injury treatment.

Lifetime imaging of endogenous metabolic coenzymes is sensitive to dynamic changes in macrophage activation in a live animal, providing a label-free imaging approach to study immunometabolism in vivo with single-cell, spatial, and temporal resolution.

The role of macrophages in osteoarthritis and cartilage repair

Macrophages are important players in the immune system that sense various tissue challenges and trigger inflammation. Tissue injuries are followed by inflammation, which is tightly coordinated with tissue repair processes. Dysregulation of these processes leads to chronic inflammation or tissue fibrosis. Wnt ligands are present both in homeostatic and pathological conditions. However, their roles and mechanisms regulating inflammation and tissue repair are being investigated. Here we aim to provide an overview of overarching themes regarding Wnt and macrophages by reviewing the previous literature. We aim to gain future insights into how tissue inflammation, repair, regeneration, and fibrosis events are regulated by macrophages.

Macrophages play a vital role in tissue repair and regeneration following injury. However, the cell fate, dynamic responses, and functions of macrophages from various origins during lung injury and repair are not fully understood. Here, we used genetic lineage tracing and scRNA-seq approaches to explore the temporal and spatial roles of tissue-resident and infiltrating macrophages during pulmonary fibrosis. We observed a sharp reduction in tissue-resident macrophages during the early inflammatory phase, with their numbers stabilizing during recovery. Monocytes contributed substantially to the macrophage population during the fibrotic phase, initially differentiating into interstitial macrophages and later transitioning into alveolar macrophages through a transient state. Genetic ablation of monocytes led to a reduction in the number of infiltrating macrophages and alleviated pulmonary fibrosis. Mechanistically, Notch signaling was negatively correlated with Wnt/β-catenin signaling in the regulation of monocyte recruitment and pulmonary fibrosis. Our study reveals the dynamic contributions and functions of macrophages from various sources in lung injury and regeneration.

死细胞释放的病原相关分子模式(pathogen-associated molecule patterns, PAMP)和损伤相关分子模式(damageassociated molecule patterns, DAMP)

Inflammation is an essential host defense mechanism in response to microbial infection and tissue injury. In addition to its well-established role in infection, inflammation is actively involved in the repair of damaged tissues and restoration of homeostatic conditions after tissue injury. The intensity of the inflammatory response and types of cells involved in inflammation have a significant impact on the quality of tissue repair. Numerous immune cell subtypes participate in tissue repair and regeneration. In particular, immune cell-derived secretants, including cytokines and growth factors, can actively modulate the proliferation of resident stem cells or progenitor cells to facilitate tissue regeneration. These findings highlight the importance of inflammation during tissue repair and regeneration; however, the precise role of immune cells in tissue regeneration remains unclear. In this review, we summarize the current knowledge on the contribution of specific immune cell types to tissue repair and regeneration. We also discuss how inflammation affects the final outcome of tissue regeneration.

Glucosamine regulates macrophage function in heart failure.

The repair strategy after organs injuries has always been a hot topic in the field of regenerative medicine. Traditional injury repair measures mainly promote tissue repair through mesenchymal stem cells and various growth factors, but these strategies have been constrained in the aspects of security and economy. Hence, there is an urgent need to find new ways to promote tissue repair and regeneration. There have been a lot of evidences showing that the immune system plays an important role in tissue regeneration and repair. In recent years, more and more studies have been done on adaptive immunity in tissue repair, especially the regulatory T cells. Some evidences indicate that regulatory T cells participate in damage tissue repair and regeneration of multiple organs and tissue. This review briefly introduces the new advances in the repair effects and regulatory mechanism of regulatory T cells in different organ injuries, in order to provide new ideas for designing advanced repair materials with good immunoregulatory functions.

The Janus-like Face of IL-4Rα in Macrophages during Liver Fibrosis

Sectm1a Facilitates Protection against Inflammation-Induced Organ Damage through Promoting TRM Self-Renewal

This final chapter of Volume 1 is dedicated to the healing process following tissue injury that is one of the characteristic functions of the innate immune system aimed at restoring homeostasis. The two major phases of wound healing consist of initial resolution of inflammation followed by tissue regenerative and repairing processes. A variety of hematopoietic and non-hematopoietic cells of the innate immune system is regarded as the principal regulators of tissue repair and regeneration. These cells include macrophages and myofibroblasts with pronounced fibrogenic properties but also vascular cells, epithelial cells, organ-specific cells such as renal tubular cells and hepatic stellate cells, and, last but not least, stem cells, particularly, mesenchymal stem cells. Increasing evidence from the literature suggests that the activity of all these PRM-bearing cells is regulated and orchestrated by tissue injury-induced emission of DAMPs. However, the failure to resolve inflammation, combined with uncontrolled overshooting repairing pathways, leads to tissue remodelling rather than tissue regeneration, which is clinically termed as tissue fibrosis or sclerosis. This deleterious development of a progressively irreversible fibrotic response may occur when the well-defined and fine-tuned chronology of regulated inflammatory events needed for optimal repair gets out of control. These new insights into mechanisms of DAMP-promoted regenerative and repairing mechanisms are increasingly understood. Deciphering the action of DAMPs according to the nature and strength of a given perpetual or chronic repetitive injury may become the key in interfering with those deleteriously overshooting repairing processes and, thus, could open new avenues of treatment or even prevention of chronic fibrotic/sclerotic disorders such as atherosclerosis.

Therapeutic Tissue Regeneration by a Macrophage Colony-Stimulating Factor Fc Conjugate

Dickkopf1: An immunomodulatory ligand and Wnt antagonist in pathological inflammation