Macrophages in tissue repair and regeneration
Macrophages represent the first line of defense in their resident tissues and serve as a unique leukocyte population by actively coordinating homeostasis, defense mechanisms and resolution of inflammation. Macrophages are an important source of chemokines, matrix metalloproteinases and other inflammatory mediators that drive the initial cellular response following injury [53]. After the early inflammatory phase subsides, the predominant macrophage population polarize to a wound healing phenotype that is characterized by the production of numerous growth factors including PDGF, TGF-β1, IGF-1, and VEGF-α, that promote cellular proliferation, mucosal wound healing and blood vessel development [53-55]. They also produce soluble mediators that stimulate local and recruited tissue fibroblasts to differentiate into myofibroblasts, that facilitate wound contraction and closure as well as the synthesis of extracellular matrix components [53]. The proliferation and expansion of neighbouring parenchymal and stromal cells are also regulated by macrophages, and if the injury is severe, macrophages can also activate additional stem cell and local progenitor cell populations that participate in repair. Thereafter, monocytes and/or macrophages exhibiting a mostly anti-inflammatory phenotype become the dominant population [53]. Macrophages respond to and secret IL-10, TGF-β and other inhibitory mediators, including cell surface receptors like PD-L1 and PD-L2 that play a major role in the tissue repair process [53] [56]. Both clinical and in vivo studies have shown an association of early onset inflammatory bowel disease (IBD) with IL-10 or IL-10 receptor mutations in intestinal chemokine receptor CX3CR1-expressing resident macrophage. These data demonstrate that macrophage-derived IL-10 is dispensable for gut homeostasis [45]. Moreover, several studies have observed the role of macrophages in regeneration, wound closure, angiogenesis, and clearance of dead and aged cells [54, 57]. Therefore, elucidating the mechanisms by which macrophages promote tissue regeneration at a requisite micro-environment may divulge strategies for the regeneration of injured organs.
Mounting evidence suggest different monocyte and macrophage population possess distinct and non-redundant roles in tissue repair, fibrosis, and regeneration [24]. The mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue regenerating properties in various organ systems is not well understood [58]. Although effective wound repair and tissue regeneration is often associated with the preferential expansion of local tissue macrophages exhibiting an anti-inflammatory phenotype, when the injury is locally severe or chronic, additional inflammatory monocytes may also be required to restore normal tissue architecture. Nevertheless, the rapid conversion of these pro-inflammatory TNF-α producing macrophages to an anti-inflammatory IL-10 and TGF-β1 producing phenotype appears to be critical to the long-term survival of stem and progenitor cell populations in most tissues [59]. Thus, to facilitate effective organ regeneration and prevent fibrosis, the monocyte and macrophage response must be finely tuned.
Macrophage secreted tissue repair mediators, like TGF-β, IL-10, IL-23 which are essential for the remodelling phase of wound healing, can be directed to treat gut leakage. Further IL-33, IL-4, IL-13 from macrophages are found to be capable of activating wound healing macrophages [60]. In addition, emerging pro-repair mediators like Granulin [61] and Plet1 [62], a wound repair mediator, have been recently shown to be expressed by resident alveolar macrophages and intestinal dendritic cells [63, 64]. Moreover, a deficiency of intestinal macrophages may increase susceptibility to infection and inhibit the activity of tissue repair. These studies suggest a promising role of these proteins as therapeutic agents to treat gut inflammation and gut leakage. However, the mode of delivery and mechanism of action has to be carefully considered during investigations. Taken together, macrophages are crucially involved in many aspects of wound healing. Depending
on their polarization and the phase of wound healing, they may promote wound closure. Identifying mechanisms that support repair, and understanding how these pathways are dysregulated in disease, are key to improving resolution of intestinal tissue damage during gut leakage.