Phagocytes orchestrate acute inflammation and host defense. Here we carried out lipid mediator (LM) metabololipidomics profiling distinct phagocytes: neutrophils (PMN), apoptotic PMN, and ...macrophages. Efferocytosis increased specialized pro-resolving mediator (SPM) biosynthesis, including Resolvin D1 (RvD1), RvD2, and RvE2, which were further elevated by PMN microparticles. Apoptotic PMN gave elevated prostaglandin E2, lipoxin B4 and RvE2, whereas zymosan-stimulated PMN showed predominantly leukotriene B4 and 20-OH-leukotriene B4, as well as lipoxin marker 5,15-diHETE. Using deuterium-labeled precursors (d8-arachidonic acid, d5-eicosapentaenoic acid, and d5-docosahexaenoic acid), we found that apoptotic PMN and microparticles contributed to SPM biosynthesis during efferocytosis. M2 macrophages produced SPM including maresin-1 (299 ± 8 vs 45 ± 6 pg/2.5 × 105 cells; P < .01) and lower amounts of leukotriene B4 and prostaglandin than M1. Apoptotic PMN uptake by both macrophage subtypes led to modulation of their LM profiles. Leukotriene B4 was down-regulated in M2 (668 ± 81 vs 351 ± 39 pg/2.5 × 105 cells; P < .01), whereas SPM including lipoxin A4 (977 ± 173 vs 675 ± 167 pg/2.5 × 105 cells; P < .05) were increased. Conversely, uptake of apoptotic PMN by M2 macrophages reduced (∼ 25%) overall LM. Together, these results establish LM signature profiles of human phagocytes and related subpopulations. Moreover, they provide evidence for microparticle regulation of specific endogenous LM during defined stages of the acute inflammatory process and their dynamic changes in human primary phagocytes.
Inflammatory diseases are a major socio‐economic burden, with the incidence of such conditions on the rise, especially in western societies. For decades, the primary treatment paradigm for many of ...these conditions was to develop drugs that inhibit or antagonize the production and biological actions of molecules that were thought to be the culprits in propagating disease; these include cytokines and eicosanoids. This approach is effective in controlling disease propagation; however, long‐term exposure to these anti‐inflammatories is also associated with many side effects, some of which are severe, including immune‐suppression. The discovery that termination of self‐limited acute inflammation is an active process orchestrated by endogenous mediators, including the essential fatty acid‐derived resolvins, protectins and maresins, has provided novel opportunities for the design of therapeutics that control inflammation with a lower burden of side effects. This is because at variance to anti‐inflammatories, pro‐resolving mediators do not completely inhibit inflammatory responses; instead, these mediators reprogramme the immune response to accelerate the termination of inflammation, facilitating the regain of function. The scope of this review is to highlight the biological actions of these autacoids and their potential utility as lead compounds in developing resolution pharmacology‐based therapeutics.
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This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc
Highlights • Biosynthesis of specialized proresolving mediators (SPM). • Functions of resolvins, lipoxins, protectins and maresins. • SPM actions in animal models of disease.
Endogenous mechanisms that orchestrate resolution of acute inflammation are essential in host defense and the return to homeostasis. Resolvin (Rv)D2 is a potent immunoresolvent biosynthesized during ...active resolution that stereoselectively stimulates resolution of acute inflammation. Here, using an unbiased G protein-coupled receptor-β-arrestin-based screening and functional sensing systems, we identified a receptor for RvD2, namely GPR18, that is expressed on human leukocytes, including polymorphonuclear neutrophils (PMN), monocytes, and macrophages (MΦ). In human MΦ, RvD2-stimulated intracellular cyclic AMP was dependent on GPR18. RvD2-stimulated phagocytosis of Escherichia coli and apoptotic PMN (efferocytosis) were enhanced with GPR18 overexpression and significantly reduced by shRNA knockdown. Specific binding of RvD2 to recombinant GPR18 was confirmed using a synthetic (3)H-labeled-RvD2. Scatchard analysis gave a Kd of ∼10 nM consistent with RvD2 bioactive concentration range. In both E. coli and Staphylococcus aureus infections, RvD2 limited PMN infiltration, enhanced phagocyte clearance of bacteria, and accelerated resolution. These actions were lost in GPR18-deficient mice. During PMN-mediated second organ injury, RvD2's protective actions were also significantly diminished in GPR18-deficient mice. Together, these results provide evidence for a novel RvD2-GPR18 resolution axis that stimulates human and mouse phagocyte functions to control bacterial infections and promote organ protection.
Mounting of the acute inflammatory response is crucial for host defense and pivotal to the development of chronic inflammation, fibrosis, or abscess formation versus the protective response and the ...need of the host tissues to return to homeostasis. Within self-limited acute inflammatory exudates, novel families of lipid mediators are identified, named resolvins (Rv), protectins, and maresins, which actively stimulate cardinal signs of resolution, namely, cessation of leukocytic infiltration, counterregulation of proinflammatory mediators, and the uptake of apoptotic neutrophils and cellular debris. The biosynthesis of these resolution-phase mediators in sensu stricto is initiated during lipid-mediator class switching, in which the classic initiators of acute inflammation, prostaglandins and leukotrienes (LTs), switch to produce specialized proresolving mediators (SPMs). In this work, we review recent evidence on the structure and functional roles of these novel lipid mediators of resolution. Together, these show that leukocyte trafficking and temporal spatial signals govern the resolution of self-limited inflammation and stimulate homeostasis.
Macrophages are central in coordinating the host response to both sterile and infective insults. Clearance of apoptotic cells and cellular debris is a key biological action preformed by macrophages ...that paves the way to the resolution of local inflammation, repair and regeneration of damaged tissues, and re-establishment of function. The essential fatty acid-derived autacoids termed specialized pro-resolving mediators (SPM) play central roles in promoting these processes. In the present article, we will review the role of microvesicles in controlling macrophage efferocytosis and SPM production. We will also discuss the role of both apoptotic cells and microvesicles in providing substrate for transcellular biosynthesis of several SPM families during efferocyotsis. In addition, this article will discuss the biological actions of the recently uncovered macrophage-derived SPM termed maresins. These mediators are produced via 14-lipoxygenation of docosahexaenoic acid that is either enzymatically converted to mediators carrying two hydroxyl groups or to autacoids that are peptide-lipid conjugates, coined maresin conjugates in tissue regeneration. The formation of these mediators is temporally regulated during acute self-limited infectious-inflammation where they promote the uptake and clearance of apoptotic cells, regulate several aspects of the tissue repair and regeneration, and display potent anti-nociceptive actions.
Acute inflammatory responses are protective, yet without timely resolution can lead to chronic inflammation and organ fibrosis. A systems approach to investigate self-limited (self-resolving) ...inflammatory exudates in mice and structural elucidation uncovered novel resolution phase mediators in vivo that stimulate endogenous resolution mechanisms in inflammation. Resolving inflammatory exudates and human leukocytes utilize DHA and other n−3 EFA to produce three structurally distinct families of potent di- and trihydroxy-containing products, with several stereospecific potent mediators in each family. Given their potent and stereoselective picogram actions, specific members of these new families of mediators from the DHA metabolome were named D-series resolvins (Resolvin D1 to Resolvin D6), protectins (including protectin D1–neuroprotectin D1), and maresins (MaR1 and MaR2). In this review, we focus on a) biosynthesis of protectins and maresins as anti-inflammatory–pro-resolving mediators; b) their complete stereochemical assignments and actions in vivo in disease models. Each pathway involves the biosynthesis of epoxide-containing intermediates produced from hydroperoxy-containing precursors from human leukocytes and within exudates. Also, aspirin triggers an endogenous DHA metabolome that biosynthesizes potent products in inflammatory exudates and human leukocytes, namely aspirin-triggered Neuroprotectin D1/Protectin D1 AT-(NPD1/PD1). Identification and structural elucidation of these new families of bioactive mediators in resolution has opened the possibility of diverse patho-physiologic actions in several processes including infection, inflammatory pain, tissue regeneration, neuroprotection-neurodegenerative disorders, wound healing, and others. This article is part of a Special Issue entitled “Oxygenated metabolism of PUFA: analysis and biological relevance”.
•Proresolving mediators are biosynthesized during resolution phase of acute inflammation.•Resolution is a biosynthetically active process.•Protectins and maresins are two structurally distinct families of potent local mediators.•NPD1/PD1 reduces neural inflammation, stimulates resolution and reduces pain.•MaR1 stimulates tissue regeneration and resolution mechanisms, is anti-inflammatory and reduces pain.
Uncovering mechanisms that control immune responses in the resolution of bacterial infections is critical for the development of new therapeutic strategies that resolve infectious inflammation ...without unwanted side effects. We found that disruption of the vagal system in mice delayed resolution of Escherichia coli infection. Dissection of the right vagus decreased peritoneal group 3 innate lymphoid cell (ILC3) numbers and altered peritoneal macrophage responses. Vagotomy resulted in an inflammatory peritoneal lipid mediator profile characterized by reduced concentrations of pro-resolving mediators, including the protective immunoresolvent PCTR1, along with elevated inflammation-initiating eicosanoids. We found that acetylcholine upregulated the PCTR biosynthetic pathway in ILC3s. Administration of PCTR1 or ILC3s to vagotomized mice restored tissue resolution tone and host responses to E. coli infections. Together these findings elucidate a host protective mechanism mediated by ILC3-derived pro-resolving circuit, including PCTR1, that is controlled by local neuronal output to regulate tissue resolution tone and myeloid cell responses.
•Vagotomy reduces tissue PCTR1 amounts and ILC3 numbers, delaying infection resolution•ILC3 depletion alters peritoneal macrophage phenotype and reduces peritoneal PCTR1•Acetylcholine upregulates the PCTR pathway in mouse and human ILC3s•ILC3 or PCTR1 restores peritoneal macrophage responses and resolution of infections
Resolution of the inflammatory response to infections is important to prevent damage to the host. Dalli et al. find that the vagus nerve promotes bacterial clearance by regulating tissue ILC3 numbers and upregulating the protective mediator PCTR1, which conditions peritoneal macrophage responses and promotes resolution of infection.
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Several novel oxygenated polyunsaturated lipid mediators biosynthesized from n-3 docosapentaenoic acid were recently isolated from murine inflammatory exudates and human primary ...cells. These compounds belong to a distinct family of specialized pro-resolving mediators, and display potent in vivo anti-inflammatory and pro-resolution effects. The endogenously formed specialized pro-resolving mediators have attracted a great interest as lead compounds in drug discovery programs towards the development of new classes of drugs that dampen inflammation without interfering with the immune response. Detailed information on the chemical structures, cellular functions and distinct biosynthetic pathways of specialized pro-resolving lipid mediators is a central aspect of these biological actions. Herein, the isolation, structural elucidation, biosynthetic pathways, total synthesis and bioactions of the n-3 docosapentaenoic acid derived mediators PD1n-3 DPA and MaR1n-3 DPA are discussed. In addition, a brief discussion of a novel family of mediators derived from n-3 docosapentaenoic acid, termed 13-series resolvins is included.
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