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.