Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators

Abstract

Active resolution of acute inflammation is a previously unrecognized interface between innate and adaptive immunity. Once thought to be a passive process, the resolution of inflammation is now shown to involve active biochemical programmes that enable inflamed tissues to return to homeostasis. This Review presents new cellular and molecular mechanisms for the resolution of inflammation, revealing key roles for eicosanoids, such as lipoxins, and recently discovered families of endogenous chemical mediators, termed resolvins and protectins. These mediators have anti-inflammatory and pro-resolution properties, thereby protecting organs from collateral damage, stimulating the clearance of inflammatory debris and promoting mucosal antimicrobial defence.

Figure 1. Decision paths in acute inflammation: resolution or chronic inflammation and the roles of endogenous chemical mediators

(Left) Microbial invasion of the host, injury from outside or the loss of barrier function initiates the release of exogenous chemoattractants, such as microbial peptides or endotoxins, that can activate leukocyte surface receptors, including Toll-like receptors and seven-transmembrane G-protein-coupled receptors. Signalling through these receptors initiates antimicrobial activities and further leukocyte recruitment and the formation and release of endogenous chemical mediators. Microorganisms taken up by phagocytosis activate bacterial killing mechanisms in, for example, neutrophils after complete phagosomal and phagolysosomal vacuole formation, termed complete phagocytosis. (Left lower) Injury from within as in surgical trauma and ischemia-reperfusion injury also activates the release of endogenous chemical mediators, such as leukotriene B₄, prostaglandin E₂ and C5a. Both exogenous and endogenous chemoattractant gradients stimulate the recruitment of neutrophils via diapedesis from postcapillary venules, an event that is amplified by the production of local leukotriene B₄. During the tissue progression of inflammatory events, intravascular platelet-leukocyte interactions evoke the formation of lipoxin A₄ and lipoxin B₄, which stop further recruitment of neutrophills and stimulate nonphlogistic monocyte infiltration. (Right) The outcome of acute inflammation — resolution, chronicity and fibrosis — may be influenced by many factors, such as the nature and intensity of the injury, the location of the injury and the over-responsiveness of the host, which is broadly controlled by both genetic and nutritional elements. The return from inflammation to normal homeostasis (complete resolution) is an actively regulated programme at the tissue level, coined catabasis. Specific prostaglandins (PGE₂ and PGD₂) and leukotriene B₄ are involved in the initiation and amplification of acute inflammation. Both PGE₂ and PGD₂ stimulate the switching of arachidonic-acid-derived lipids from LTB₄ production to lipoxin A₄ production, for example, and then the switching of lipid mediator families to produce anti-inflammatory and pro-resolution lipid mediators, such as E-series and D-series resolvins and protectins. Alternatively, chronic inflammation can result from excessive and/or unresolved inflammatory responses and can lead to chronic disorders. Arachidonic-acid-derived lipid mediators such as pro-inflammatory prostaglandins and leukotrienes can amplify this process. Fibrosis can occur when inflammatory injury causes substantial tissue destruction, connective tissue replacement occurs and results in loss of tissue function.

Figure 1. Decision paths in acute inflammation: resolution or chronic inflammation and the roles of endogenous chemical mediators

(Left) Microbial invasion of the host, injury from outside or the loss of barrier function initiates the release of exogenous chemoattractants, such as microbial peptides or endotoxins, that can activate leukocyte surface receptors, including Toll-like receptors and seven-transmembrane G-protein-coupled receptors. Signalling through these receptors initiates antimicrobial activities and further leukocyte recruitment and the formation and release of endogenous chemical mediators. Microorganisms taken up by phagocytosis activate bacterial killing mechanisms in, for example, neutrophils after complete phagosomal and phagolysosomal vacuole formation, termed complete phagocytosis. (Left lower) Injury from within as in surgical trauma and ischemia-reperfusion injury also activates the release of endogenous chemical mediators, such as leukotriene B₄, prostaglandin E₂ and C5a. Both exogenous and endogenous chemoattractant gradients stimulate the recruitment of neutrophils via diapedesis from postcapillary venules, an event that is amplified by the production of local leukotriene B₄. During the tissue progression of inflammatory events, intravascular platelet-leukocyte interactions evoke the formation of lipoxin A₄ and lipoxin B₄, which stop further recruitment of neutrophills and stimulate nonphlogistic monocyte infiltration. (Right) The outcome of acute inflammation — resolution, chronicity and fibrosis — may be influenced by many factors, such as the nature and intensity of the injury, the location of the injury and the over-responsiveness of the host, which is broadly controlled by both genetic and nutritional elements. The return from inflammation to normal homeostasis (complete resolution) is an actively regulated programme at the tissue level, coined catabasis. Specific prostaglandins (PGE₂ and PGD₂) and leukotriene B₄ are involved in the initiation and amplification of acute inflammation. Both PGE₂ and PGD₂ stimulate the switching of arachidonic-acid-derived lipids from LTB₄ production to lipoxin A₄ production, for example, and then the switching of lipid mediator families to produce anti-inflammatory and pro-resolution lipid mediators, such as E-series and D-series resolvins and protectins. Alternatively, chronic inflammation can result from excessive and/or unresolved inflammatory responses and can lead to chronic disorders. Arachidonic-acid-derived lipid mediators such as pro-inflammatory prostaglandins and leukotrienes can amplify this process. Fibrosis can occur when inflammatory injury causes substantial tissue destruction, connective tissue replacement occurs and results in loss of tissue function.

Figure 2. Dual anti-inflammatory and pro-resolution actions of specific lipoxins, resolvins and protectins

The key histological feature in resolution is the loss of neutrophils from the local inflamed sites. This is a programmed process that is actively regulated at multiple levels: by reducing neutrophil infiltration into the exudates, increasing monocyte recruitment, stimulating macrophage uptake of apoptotic neutrophils, and promoting phagocyte removal via the lymphatics.

Figure 3. Mechanisms of action of lipoxin A₄ and resolvin E1: regulation at multiple levels via GPCRs

(A) Lipoxin A₄: two main “classic” lipoxygenase-mediated pathways of lipoxin generation appear to be used in human cells and tissues (in the vasculature and at mucosal surfaces). The overall action of lipoxin A₄in vivo is likely to be attributed to its interactions with G-protein-coupled receptors (GPCRs) and growth-factor receptors. Direct activation of the lipoxin A₄ receptor (denoted ALX) by lipoxin A₄ has cell-type-specific signalling events that stop neutrophil migration and stimulate monocytes and macrophages. Indirect inhibition, via receptor crosstalk, of other GPCRs (such as leukotriene B₄ receptor, denoted BLT1) and growth-factor receptors (such as VEGF on endothelium and PDGF and CTGF on mesangial cells) by lipoxin A₄ reduces angiogenesis and mesangial-cell proliferation and fibrosis. (B) Resolvin E1: Aspirin acetylates cyclooxygenase-2 (COX2) in vascular endothelial cells and generates 18R-hydroperoxyeicosapentaenoic acid (18R-HPEPE), which is further converted via 5-lipoxygenase in leukocytes and additional enzymatic reactions to form resolvin E1. Microbial cytochrome P450 enzymes can also contribute to resolvin E biosynthesis by converting eicosapentaenoic acid (EPA) to 18-HEPE. Resolvin E1 directly interacts with at least two G-protein-coupled receptor (GPCR) systems in a cell-type-specific manner. Resolvin E1 directly activates ChemR23 on mononuclear cells and dendritic cells and directly inhibits the leukotriene B₄ receptor, denoted BLT1, on human neutrophils.

Figure 3. Mechanisms of action of lipoxin A₄ and resolvin E1: regulation at multiple levels via GPCRs

(A) Lipoxin A₄: two main “classic” lipoxygenase-mediated pathways of lipoxin generation appear to be used in human cells and tissues (in the vasculature and at mucosal surfaces). The overall action of lipoxin A₄in vivo is likely to be attributed to its interactions with G-protein-coupled receptors (GPCRs) and growth-factor receptors. Direct activation of the lipoxin A₄ receptor (denoted ALX) by lipoxin A₄ has cell-type-specific signalling events that stop neutrophil migration and stimulate monocytes and macrophages. Indirect inhibition, via receptor crosstalk, of other GPCRs (such as leukotriene B₄ receptor, denoted BLT1) and growth-factor receptors (such as VEGF on endothelium and PDGF and CTGF on mesangial cells) by lipoxin A₄ reduces angiogenesis and mesangial-cell proliferation and fibrosis. (B) Resolvin E1: Aspirin acetylates cyclooxygenase-2 (COX2) in vascular endothelial cells and generates 18R-hydroperoxyeicosapentaenoic acid (18R-HPEPE), which is further converted via 5-lipoxygenase in leukocytes and additional enzymatic reactions to form resolvin E1. Microbial cytochrome P450 enzymes can also contribute to resolvin E biosynthesis by converting eicosapentaenoic acid (EPA) to 18-HEPE. Resolvin E1 directly interacts with at least two G-protein-coupled receptor (GPCR) systems in a cell-type-specific manner. Resolvin E1 directly activates ChemR23 on mononuclear cells and dendritic cells and directly inhibits the leukotriene B₄ receptor, denoted BLT1, on human neutrophils.

Figure 4. Resolution indices pinpoint the tissue level mechanism of action of anti-inflammatory-pro-resolution lipid mediators

(Upper part) The main events in resolution of acute inflammation can be quantified by introducing resolution indices: (i) Magnitude (Ψ_max, T_max) -- The time point (T_max) when neutrophil numbers reach maximum (Ψ_max); (ii) Duration (R₅₀, T₅₀) -- The time point (T₅₀) when the neutrophil numbers reduce to 50% of Ψ_max (R₅₀); (iii) Resolution Interval (R_i) --The time interval from the maximum neutrophil point (Ψ_max) to the 50% reduction point (R₅₀) [i.e. T₅₀ - T_max]. For calculating specific resolution indices, see refs. 8 and for details. ATLa lowers the maximal neutrophil numbers (↓Ψ_max); RvE1 and PD1, in addition, initiate the resolution at the earlier time (↓T_max and T₅₀); PD1 further shortens the resolution interval (↓R_i). (Lower part) The resolution agonists lipoxins, resolvins and protectins promote homeostasis by stimulating exudate cells and surrounding tissues to limit further neutrophil infiltration; increase CC-chemokine receptor 5 (CCR5) expression on apoptotic neutrophils and lymphocytes, which enhances the removal of chemokines and cytokines that adhere to dying leukocytes and are transported out of the tissues and phagocytosed by macrophages (for detailed mechanism, see ref 73); promote macrophage uptake of neutrophils in the exudates and the removal of macrophages carrying such debris; enhance the clearance of zymosan-engulfed leukocytes in lymph nodes and in spleen; stimulate the antimicrobial actions and clearance mechanisms of mucosal epithelial-cell surfaces, .