Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?

Abstract

Because inflammation is appreciated as a unifying basis of many widely occurring diseases, the mechanisms involved in its natural resolution are of considerable interest. Using contained, self-limited inflammatory exudates and a systems approach, novel lipid-derived mediators and pathways were uncovered in the resolution of inflammatory exudates. These new families of local mediators control both the duration and magnitude of acute inflammation as well as the return of the site to homeostasis in the process of catabasis. This new genus of specialized proresolving mediators (SPM) includes essential fatty acid-derived lipoxins, resolvins, protectins, and, most recently, maresins. These families were named based on their unique structures and potent stereoselective actions. The temporally initiated biosynthesis of SPM and their direct impact on leukocyte trafficking and macrophage-directed clearance mechanisms provide clear evidence that resolution is an active, programmed response at the tissue level. Moreover, SPM that possess anti-inflammatory (ie, limiting PMN infiltration) and proresolving (enhance macrophage uptake and clearance of apoptotic PMN and microbial particles) actions as well as stimulating mucosal antimicrobial responses demonstrate that anti-inflammation and proresolution are different responses of the host and novel defining properties of these molecules. The mapping of new resolution circuits has opened the possibility for understanding mechanisms that lead from acute to chronic inflammation, or to the resolution thereof, as well as to potential, resolution-based immunopharmacological therapies.

Figure 1

Decision paths in acute inflammation: resolution or chronic inflammation? Lipid mediators such as prostaglandins and leukotrienes play specific roles in the physiology of the acute inflammatory response. They can regulate many of the cardinal signs of inflammation. Self-limited inflammatory exudates permitted the identification and study of specialized pro-resolving mediators that stimulate the return to homeostasis.

Figure 2

Ideal outcome of acute inflammation: complete resolution. Using a systems approach to mapping resolution, temporal and spatial dissociation of eicosanoids was uncovered, which is termed lipid mediator class switching. Prostaglandins and leukotrienes are generated early in the response. Prostaglandins E₂ and D₂ stimulate the transcriptional regulation in human leukocytes for the production of enzymes required for lipoxin biosynthesis. Unresolved acute inflammation is associated with increased prostaglandin and leukotriene production and chronic inflammation. Inset: Experimental acute inflammation shows the temporal theoretical events in edema formation and its decline as well as leukocyte trafficking with nonphlogistic recruitment of PMNs. During the decline of PMNs, specialized proresolving mediators are temporally produced in vivo in inflammatory exudates; see text for details.

Figure 3

The genus of specialized proresolving mediators: structures and actions. The SPM genus is defined by reduction or limiting further PMN infiltration and reduction of lipid mediators and cytokines. SPM also stimulate the nonphlogistic recruitment of mononuclear cells and the stimulation of macrophages to phagocytose apoptotic PMN microbes and microbial particles. The family precursors are substrates for their respective conversion to lipoxins, E-series resolvins, D-series resolvins, and protectins. The main structures of key SPM genus members are depicted; the complete stereochemistry of each has been determined, and their physical properties and bioactions have been confirmed by total organic synthesis; see text for details.

Figure 4

SPM-regulated processes in resolution and a new role for edema in delivering essential fatty acids. This illustration depicts a self-limited evolving exudate with the key roles of specialized proresolving mediators (SPM), substrate delivery, and leukocyte trafficking. i) Lower right-hand corner: microbial invasion in injury initiates chemotactic signals that initially summon neutrophils from postcapillary venules. Neutrophils arrive to the site via diapedesis and chemotaxis. A key chemoattractant of the eicosanoids in the process is leukotriene B₄. There is also a wide range of cytokines and chemokines that stimulate neutrophil recruitment in this important and fundamental process. ii) As neutrophils congregate in the contained inflammatory exudate, cell–cell interactions (eg, with platelets in transcellular biosynthesis generated between PMN and platelets) initiate the transcellular biosynthesis of lipoxins. Newly arrived and older PMN within the exudate interact to produce resolvins and protectins via transcellular biosynthesis. During this process, edema carries the ω-3 essentially fatty acids EPA and DHA from the blood into the exudate for their utilization. iii) Once resolvins and protectins are produced, these SPM stimulate macrophages to take up apoptotic PMN and cellular debris. Additionally, the corpses of apoptotic PMN can serve to bind chemokines and cytokines for their disposal. SPM enhance macrophage uptake and clearance. iv) Macrophages phagocytose apoptotic PMN. This process is stimulated by SPM and is an anti-inflammatory and nonphlogistic process. Rather than producing proinflammatory mediators during phagocytosis, such as LTB₄, TNF, and IL-1, these macrophages produce lipoxins, resolvins, and NPD1/PD1 that, in turn, inhibit further edema through a feedback mechanism. This hypothetical course of events and time course help the contained inflammatory exudate to resolve as well as efficiently combat infection and return to homeostasis from local tissue injury.