Box 1. Wound healing as an example of physiological inflammation
Platelet activation and aggregation, in addition to accelerating coagulation, provide a bolus of secreted proteins and α-granule contents to the immediate area, all of which help initiate and accelerate the inflammatory response by the host. Examples of such secreted proteins include arachodonic acid metabolites, heparin, serotonin, thrombin, coagulation factors (factor V), adhesive proteins (fibrinogen and von Willebrand factor), plasma proteins (immunoglobulin-γ and albumin), cell growth factors (platelet-derived growth factor (PDGF), platelet-derived angiogenesis factor, transforming growth factor-α (TGF-α), TGF-β and basic fibroblast growth factor (bFGF)), enzymes (heparanase and factor XIII) and protease inhibitors (plasminogen activator inhibitor-1, α2-macroglobulin and α2-antiplasmin). Following platelet-induced haemostasis and release of TGF-β1 and PDGF, formation of granulation tissue is facilitated by chemotaxis of neutrophils, monocytes, fibroblasts and myofibroblasts, as well as by synthesis of new extracellular matrix (ECM) and neoangiogenesis.
Neutrophil chemotaxis is stimulated by factors such as circulating complement factor 5 (C5a), leukotriene B4, kallikrein, bacterial products (if present) and numerous factors released from platelets at the site (for example, PDGF, TGF-β, platelet-activating factor and platelet factor-4 (PF-4)). Although terminally differentiated with little biosynthetic machinery, neutrophils are capable of considerable production of cytokines/chemokines necessary for effector cell recruitment, activation and response15
. These phagocytic cells initiate wound healing by serving as a source of early-response pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α)68
, and interleukin (IL)-1α and IL-1β69
. These cytokines mediate leukocyte adherence to the vascular endothelium, thus targeting and restricting leukocytes to areas of repair, and initiate repair by inducing expression of matrix metalloproteinases (MMPs) and keratinocyte growth factor (KGF/FGF-7) by fibroblasts70
In response to tissue injury, mononuclear phagocytes (that is, macrophage progenitors) migrate from the venous system to the site of tissue injury. They are guided to the site by chemotactic factors, including PF-4, TGF-β, PDGF, chemokines (monocyte chemoattractant protein-1, -2 and -3 (MCP-1/CCL2, MCP-2/CCL8 and MCP-3/CCL7), macrophage inflammatory protein-1α and -1β (MIP-1α/CCL3 and MIP-1β/CCL4), and the cytokines IL-1β and TNF-α. Deployment of monocytes/macrophages to the site of injury peaks as the number of neutrophils decline. Once present, however, they differentiate into mature macrophages or immature dendritic cells71
. After activation, macrophages are the main source of growth factors and cytokines (TGF-β1, PDGF, bFGF, TGF-α, insulin-like growth factor (IGF)-I and -II, TNF-α and IL-1) that modulate tissue repair. Cells in their local microenvironment (for example, endothelial, epithelial, mesenchymal or neuroendocrine cells) are profoundly affected by macrophage products. Macrophages also regulate local tissue remodelling by inducing ECM components, stimulating production of proteolytic enzymes (for example, MMPs and urokinase-type plasminogen activator (uPA)), clearing apoptotic and necrotic cells, and modulating angiogenesis through local production of thrombospondin-1 (refs 72, 73
Following their activation, mast cells are full of stored and newly synthesized inflammatory mediators. This cell type synthesizes and stores histamine, cytokines and proteases complexed to highly sulphated proteoglycans within granules, and produces lipid mediators and cytokines upon stimulation. Once activated by complement or by binding of antigens to immunoglobulin E (IgE) bound to high-affinity IgE receptors (FcεRI), they degranulate, releasing mediators including heparin, heparanase, histamine, MMPs and serine proteases, and various polypeptide growth factors, including bFGF and vascular endothelial growth factor74
. These function both in the early initiation phase of inflammation (for example, vascular reaction and exudation), and in the late phase where leukocyte accumulation and wound healing takes place.
Chemokines are classified into polypeptide groups identified by the location of cysteine residues near their amino termini (for example, C-C, C-X-C, C and CX3
C). Chemokines represent the largest family of cytokines (~41 human members), forming a complex network for the chemotactic activation of all leukocytes. Chemokine receptors, members of the seven-transmembrane-spanning G-protein-coupled receptors, vary by cell type and degree of cell activation6
. There is considerable redundancy in chemokine-receptor interaction, as many ligands bind different receptors, or vice versa.
The composition of chemokines produced at sites of tissue wounding not only recruits downstream effector cells (as discussed above), but also dictates the natural evolution of immune reactivity. For example, MCP-1/CCL2, a potent chemotactic protein for monocytes and lymphocytes, simultaneously induces expression of lymphocyte-derived IL-4 in response to antigen challenge while decreasing expression of IL-12 (ref. 75
). The net effect of this alteration facilitates a switch from a TH
1-type to a TH
2-type inflammatory response.
In response to wounding, fibroblasts migrate into the wound bed and initially secrete collagen type III, which is later replaced by collagen type I. Synthesis and deposition of these collagens by fibroblasts is stimulated by factors including TGF-β1, -β2 and -β3, PDGF, IL-1α, -1β and -4, and mast cell tryptase. Once sufficient collagen has been generated, its synthesis is stopped; thus, during wound repair, production as well as the degradation of collagens is under precise spatial and temporal control.
The final phase of the healing process is re-epithelialization and migration of epithelial cells across this amalgam, in a process that requires both dissolution of the fibrin clot and degradation of the underlying dermal collagen. Epithelial cells at the leading edge of the wound express the uPA receptor, which is important for focal activation of uPA, and collagenolytic enzymes of the MMP family. In the absence of the fibrinolytic enzyme plasmin, derived from plasminogen after activation by uPA and tissue-PA, re-epithelialization is dramatically delayed76
The pro-inflammatory properties of TGF-β, such as leukocyte recruitment, adhesion and regulation of MMP secretion and activation, are balanced by its ability to also reverse its role, and suppress these events and foster ECM synthesis to mediate tissue repair8
. As inflammatory cells are activated, their complement of TGF-β receptors change, resulting in differential susceptibility to TGF-β and enhanced sensitivity to suppression by TGF-β8
, a critical event to resolving inflammation.