The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution

Abstract

Studies into the mechanisms in resolution of self-limited inflammation and acute reperfusion injury have uncovered a new genus of pro-resolving lipid mediators coined specialized pro-resolving mediators (SPM) including lipoxins, resolvins, protectins and maresins that are each temporally produced by resolving-exudates with distinct actions for return to homeostasis. SPM evoke potent anti-inflammatory and novel pro-resolving mechanisms as well as enhance microbial clearance. While born in inflammation-resolution, SPM are conserved structures with functions discovered in microbial defense, pain, organ protection and tissue regeneration, wound healing, cancer, reproduction, and neurobiology-cognition. This review covers these SPM mechanisms and other new omega-3 PUFA pathways that open their path for functions in resolution physiology.

Keywords: Essential fatty acids; Host defense; Infection; Inflammation; Lipid mediator.

Figure 1. Lipid mediators in the acute inflammatory response and its outcomes

Panel A: LM play pivotal roles in the vascular response and leukocyte trafficking, from initiation to resolution. Eicosanoids are critical in initiating the cardinal signs of inflammation, and the specialized proresolving mediators (SPM), illustrated above, play key roles stimulating resolution (Panel B). Depicted are some roles of resolvins, protectins and maresins, SPM, in leukocyte trafficking, lipid mediator class switching, efferocytosis, resolving exudates to homeostasis and signaling to adaptive immunity via lymphocytes. Failed resolution can lead to enhanced prostaglandin and leukotriene production and chronic inflammation that can lead to fibrosis. SPM (lipoxins, resolvins, protectins and maresins) counterregulate pro-inflammatory chemical mediators, reducing inflammation, and stimulate reepithelialization, wound healing, and tissue regeneration (see text for details).

Figure 1. Lipid mediators in the acute inflammatory response and its outcomes

Panel A: LM play pivotal roles in the vascular response and leukocyte trafficking, from initiation to resolution. Eicosanoids are critical in initiating the cardinal signs of inflammation, and the specialized proresolving mediators (SPM), illustrated above, play key roles stimulating resolution (Panel B). Depicted are some roles of resolvins, protectins and maresins, SPM, in leukocyte trafficking, lipid mediator class switching, efferocytosis, resolving exudates to homeostasis and signaling to adaptive immunity via lymphocytes. Failed resolution can lead to enhanced prostaglandin and leukotriene production and chronic inflammation that can lead to fibrosis. SPM (lipoxins, resolvins, protectins and maresins) counterregulate pro-inflammatory chemical mediators, reducing inflammation, and stimulate reepithelialization, wound healing, and tissue regeneration (see text for details).

Figure 2. Production of SPM by resolving inflammatory exudates

Panel A depicts pus formation, e.g. a purulent exudate beginning with the postcapillary venule and the diapedesis of neutrophils as they are summoned by chemoattractants to leave the vascular circulation to combat invading microbes or foreign objects. The endothelial cell interactions with PMN are a site for E-series resolvin biosynthesis (see text for details). Panel B depicts the time course of self-limited acute inflammatory response, edema, followed by neutrophilic infiltration and nonphlogistic recruitment of monocytes/macrophages from initiation (time 0) to resolution and the uptake of apoptotic PMN by resolving macrophages (rMΦ). Initial biosynthesis of SPM occurs at maximal neutrophilic infiltration through resolution in self-limiting responses. Structures of SPM: D-series resolvins, protectins and (Panel C) maresins. Depicted are resolvins D1–D4, which carry potent actions. 17-HpDHA is also precursor to 16,17-epoxide-protectin intermediate that is converted to protectin D1/neuroprotectin D1 and related protectins such as PDx, 10S,17S-diHDHA. Panel C: Maresins are produced by macrophages via initial lipoxygenation at carbon-14 position by lipoxygenation and insertion of molecular oxygen, producing a 13S,14S-epoxide-maresin intermediate that is enzymatically converted to maresin-1. The stereochemistry of each bioactive SPM is established, and SPM biosynthesis in murine exudates and human tissues confirmed. See ref. [16] for citations of original reports, total organic synthesis and stereochemical assignments and the text for further details.

Figure 2. Production of SPM by resolving inflammatory exudates

Panel A depicts pus formation, e.g. a purulent exudate beginning with the postcapillary venule and the diapedesis of neutrophils as they are summoned by chemoattractants to leave the vascular circulation to combat invading microbes or foreign objects. The endothelial cell interactions with PMN are a site for E-series resolvin biosynthesis (see text for details). Panel B depicts the time course of self-limited acute inflammatory response, edema, followed by neutrophilic infiltration and nonphlogistic recruitment of monocytes/macrophages from initiation (time 0) to resolution and the uptake of apoptotic PMN by resolving macrophages (rMΦ). Initial biosynthesis of SPM occurs at maximal neutrophilic infiltration through resolution in self-limiting responses. Structures of SPM: D-series resolvins, protectins and (Panel C) maresins. Depicted are resolvins D1–D4, which carry potent actions. 17-HpDHA is also precursor to 16,17-epoxide-protectin intermediate that is converted to protectin D1/neuroprotectin D1 and related protectins such as PDx, 10S,17S-diHDHA. Panel C: Maresins are produced by macrophages via initial lipoxygenation at carbon-14 position by lipoxygenation and insertion of molecular oxygen, producing a 13S,14S-epoxide-maresin intermediate that is enzymatically converted to maresin-1. The stereochemistry of each bioactive SPM is established, and SPM biosynthesis in murine exudates and human tissues confirmed. See ref. [16] for citations of original reports, total organic synthesis and stereochemical assignments and the text for further details.

Figure 2. Production of SPM by resolving inflammatory exudates

Panel A depicts pus formation, e.g. a purulent exudate beginning with the postcapillary venule and the diapedesis of neutrophils as they are summoned by chemoattractants to leave the vascular circulation to combat invading microbes or foreign objects. The endothelial cell interactions with PMN are a site for E-series resolvin biosynthesis (see text for details). Panel B depicts the time course of self-limited acute inflammatory response, edema, followed by neutrophilic infiltration and nonphlogistic recruitment of monocytes/macrophages from initiation (time 0) to resolution and the uptake of apoptotic PMN by resolving macrophages (rMΦ). Initial biosynthesis of SPM occurs at maximal neutrophilic infiltration through resolution in self-limiting responses. Structures of SPM: D-series resolvins, protectins and (Panel C) maresins. Depicted are resolvins D1–D4, which carry potent actions. 17-HpDHA is also precursor to 16,17-epoxide-protectin intermediate that is converted to protectin D1/neuroprotectin D1 and related protectins such as PDx, 10S,17S-diHDHA. Panel C: Maresins are produced by macrophages via initial lipoxygenation at carbon-14 position by lipoxygenation and insertion of molecular oxygen, producing a 13S,14S-epoxide-maresin intermediate that is enzymatically converted to maresin-1. The stereochemistry of each bioactive SPM is established, and SPM biosynthesis in murine exudates and human tissues confirmed. See ref. [16] for citations of original reports, total organic synthesis and stereochemical assignments and the text for further details.

Figure 3. New lipid mediators and biosynthesis routes

Panel A: SPM actions. Panel B: New routes for n-3 essential fatty acids (DHA, DPA and EPA) conversion via P450 cyclooxygenase, lipoxygenase and oxidative pathways.

Figure 3. New lipid mediators and biosynthesis routes

Panel A: SPM actions. Panel B: New routes for n-3 essential fatty acids (DHA, DPA and EPA) conversion via P450 cyclooxygenase, lipoxygenase and oxidative pathways.