Natural resolution of inflammation

Abstract

Inflammation is a protective response essential for maintaining human health and for fighting disease. As an active innate immune reaction to challenge, inflammation gives rise to clinical cardinal signs: rubor, calor, dolor, tumor and functio laesa. Termination of acute inflammation was previously recognized as a passive process; a natural decay of pro-inflammatory signals. We now understand that the natural resolution of inflammation involves well-integrated, active, biochemical programs that return tissues to homeostasis. This review focuses on recent advances in the understanding of the role of endogenous lipid mediators that modulate cellular fate and inflammation. Biosynthesis of eicosanoids and other lipids in exudates coincides with changes in the types of inflammatory cells. Resolution of inflammation is initiated by an active class switch in lipid mediators, such as classic prostaglandins and leukotrienes, to the production of proresolution mediators. Endogenous pro-resolving lipid mediators, including arachidonic acid-derived lipoxins, aspirin-triggered lipoxins, ω3-eicosapentaenoic acid-derived resolvins of the E-series, docosahexaenoic acid-derived resolvins of the D-series, protectins and maresins, are biosynthesized during the resolution phase of acute inflammation. Depending on the type of injury and the type of tissue, the initial cells that respond are polymorphonuclear leukocytes, monocytes/macrophages, epithelial cells or endothelial cells. The selective interaction of specific lipid mediators with G protein-coupled receptors expressed on innate immune cells (e.g. G protein-coupled receptor 32, lipoxin A4 receptor/formyl peptide receptor2, chemokine-like receptor 1, leukotriene B4 receptor type 1 and cabannoid receptor 2) induces cessation of leukocyte infiltration; vascular permeability/edema returns to normal with polymorphonuclear neutrophil death (mostly via apoptosis), the nonphlogistic infiltration of monocyte/macrophages and the removal (by macrophages) of apoptotic polymorphonuclear neutrophils, foreign agents (bacteria) and necrotic debris from the site. While an acute inflammatory response that is resolved in a timely manner prevents tissue injury, inadequate resolution and failure to return tissue to homeostasis results in neutrophil-mediated destruction and chronic inflammation. A better understanding of the complex mechanisms of lipid agonist mediators, cell targets and actions allows us to exploit and develop novel therapeutic strategies to treat human inflammatory diseases, including periodontal diseases.

Fig. 1

Acute inflammation and lipid mediators. The local acute inflammatory response is characterized by exudate formation and the initial recruitment of neutrophils followed by the recruitment of monocytes that differentiate into macrophages. Lipid mediators such as prostaglandins and leukotrienes, and cytokines and chemokines, regulate the well-coordinated initial events of acute inflammation. Arachidonic acid released from membrane phospholipids by phospholipase A₂ can be further metabolized by (i) cyclooxygenase-1 and cyclooxygenase-2 to generate prosta-noids, including prostaglandins and thromboxanes; (ii) lipoxygenases to generate leukotrienes and hydroxy acids; and (iii) lipoxygenase interaction products (biosynthetic pathways to generate lipoxins). Lipoxins are generated during transcellular biosynthesis, which requires two cell types involving distinct lipoxygenases. Lipid mediator class-switches yield pro-resolution lipid mediators such as lipoxin A₄ and the eicosapentaenoic acid-derived resolvins (i.e. resolvin E1 and resolvin E2) and docosahexaenoic acid-derived lipid mediators, including D-series resolvins, protectins and maresins. AT-PD1, aspirin triggered protectin D1; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HpETE, hydroperoxyeicosatetraenoic acid; LT, leukotriene; LX, lipoxin; PG, prostaglandin; PGH₂, prostaglandin H2; PLA₂, phospholipase A₂; PUFA, polyunsaturated fatty acid; Rv, resolvin; TX, thromboxane.

Fig. 2

Natural inflammation resolution response. Acute inflammation is a self-limiting response. In conditions of homeostasis, resident cells maintain normal conditions and remove apoptotic cells and debris. Upon challenge to tissue, the inflammatory response begins. Cell communication mediators activate chemoattraction, vascular permeability and infiltration of leukocytes to the periphery. Microorganisms and dead cells are taken up by phagocytes. The outcome of acute inflammation (chronicity, fibrosis or resolution) is influenced by the type of factors and the degree to which they are involved in the response. Resolution is the re-establishment of normal (homeostasis) and is an actively regulated, well-coordinated process. In resolution, inhibition of leukocyte infiltration, nonphlogistic phagocytosis and vascular and tissue function return to normal. CCL2, chemokine (C-C motif) ligand 2; CVD, cardiovascular disease; CXCL8, chemokine (C-X-C motif) ligand 8; IL, interleukin; ROS, reactive oxygen species; TNF, tumor necrosis factor.

Fig. 3

Interaction of cellular G protein-coupled receptor and lipid mediators. Biosynthesized pro-resolution lipid mediators interact selectively with G protein-coupled receptors. Receptor interactions with lipid mediators have been described in part. Lipoxin A₄ stereoselective binding to the receptors lipoxin A₄ receptor formyl peptide 2 and G protein-coupled receptor 32 activates anti-inflammation and resolution. Resolvin E1 (agonist) and the receptors chemokine-like receptor 1 and leukotriene B4 receptor type 1 have been shown to have positive influences on cell fate in inflammation. Resolvin D1 specifically interacts with both lipoxin A₄ receptor and G protein-coupled receptor 32 on phagocytes, suggesting that each plays a role in resolving acute inflammation. The specic receptor interactions for protectin D1/aspirin-triggered protectin D1 and maresin 1 are yet to be defined; however, protectin D1 lipid mediators have been suggested to target cannabinoid receptor 2, CB2. Interactions between lipid mediators and cognitive receptors were found to influence in-vitro and in-vivo cellular functions with cell-type specificity. AKT, protein kinase B; ALX/FPR2, lipoxin A4 receptor; AT-PD1, aspirin-triggered protectin D1; ATL, aspirin-triggered lipoxin; BLT-1, leukotriene B4 receptor type 1; CB2, cannabinoid receptor 2; CCR5, chemokine (C-C motif) receptor 5; chemokine-like receptor 1; GPR32, G protein-coupled receptor 32; IFN-γ, interferon gamma; IL, interleukin; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappaB; PNM, polymorphonuclear neutrophil; TNF, tumor necrosis factor.