Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators

Abstract

IntroductionInflammation is the organisms' response to local injury in vascularized tissues programmed to traffic leukocytes and plasma delivery to an injured site or point of bacterial invasion, 1 this protective response when uncontrolled in humans is associated with many widely occurring diseases. These include cardiovascular, metabolic, and the classic inflammatory diseases (ie, arthritis and periodontal disease) along with cancers. 2 Nonresolving inflammation is now widely acknowledged as a major driver in most of these diseases. 3 Resolution of inflammation and dissipation of the local chemical messengers involved in mounting the innate response were thought to be passively diluted with time at the site, hence stopping further leukocyte recruitment and resolving the exudate or battlefield of inflammation. 4,5 Results from this laboratory indicate that resolution of selflimited inflammatory exudates is a biochemically active process that involves the local and temporal biosynthesis of a new genus of specialized pro-resolving mediators (SPMs) with their novel functions mapped employing resolution indices. [5][6][7][8] SPMs encompass several families of structurally and chemically distinct mediators. These chemical mediator families include lipoxins biosynthesized from arachidonic acid, E-series resolvins (Rv) from eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)-derived D-series resolvins, protectins, and maresins. Each potent bioactive member of these families shares a defining action in resolving local inflammation. By definition, they each limit further neutrophil (PMN) recruitment to the site of injury and/or microbial invasion and enhance macrophage uptake of cellular debris and apoptotic PMN to bring about tissue homeostasis. 2 Along with these defining properties, specific SPMs carry out more specialized tasks within programmed resolution; hence, the scope of their individual actions are nonoverlapping and evoked via specific cell surface receptors that are G-protein-coupled receptors. 2 A systems approach led to the identification of novel bioactive structures coined resolvins and protectins in murine inflammatory exudates and isolated human cells based on liquid chromatography tandem mass spectrometry (LC-MS-MS)-based lipid mediator lipidomics and tandem assessment of their functions in anti-inflammation and pro-resolution. 6,9 The complete stereochemistry and total organic synthesis of several key resolvins, protectins, as well as their aspirin-triggered forms are established. 10 These include resolvin D1 (7S, 8R, 17S-trihydroxy-4Z, 9E, 11E, 13Z, 15E, 19Z-docosahexaenoic acid), resolvin D2 (7S, 16R, 17S-trihydroxy-4Z, 8E, 10Z, 12E, 14E, 19Z-DHA), 17R-HDHA (17R-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-DHA), neuroprotectin D1/NPD1 (10R, 17S-dihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-DHA), resolvin E1 (5S, 12R, 18R-trihydroxy-6Z, 8E, 10E, 14Z, 16E-eicosapentaenoic acid), and most recently maresin 1 (7R, 14S-dihydroxy-4Z,8E,10E,12Z,16Z, . 11 In addition to confirming the original structural assignments and...

Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia

“…RvD3 and its biosynthetic pathway intermediates 4-HDHA and 17-HDHA were identified in accordance with published criteria, 14 including retention time and MS-MS fragmentation spectra (Figure 1, A and B). Relative to uninjured lungs, 4-HDHA and 17-HDHA increased approximately twofold to threefold 24 hours after injury, returning to baseline levels at 72 hours ( Figure 1C Figure 1D).…”

The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation

“…18,19 We found that M1 and M2 macrophage phenotypes extend to SPMs and eicosanoid profiles. 16 M2 macrophages have elevated levels of pro-resolving lipid mediators and decreased PGs and LTs in relation to M1 macrophages. 16 By analyzing PCTR1 levels in comparison with RCTR, MCTR, and cys-LTs, we identified the distinct peptide-conjugate lipid mediator profiles of human M1 and M2 macrophages, in which pro-resolving peptide-conjugates have a reciprocal relation to the inflammatory cys-LTs ( Figure 8C).…”

“…For M1 and M2 macrophage differentiation, the previously published protocol and criteria were used. 16 In brief, M1 macrophages were produced by incubating isolated monocytes with granulocyte-macrophage CSF (20 ng/mL) for 7 days, followed by lipopolysaccharide (1 ng/mL) plus interferon-g (20 ng/mL) treatment for 24 hours. M2 macrophages were obtained by incubating monocytes with 20 ng/mL macrophage CSF for 7 days and then stimulating with 20 ng/mL IL-4 for 48 hours.…”

Changing world of neutrophils

“…In a recent study, PMNderived microparticles were shown to stimulate efferocytosis and production of pro-resolving lipid mediators in macrophages [25].…”

“…Other chemokines secreted by PMN are chemoattractants to monocytes [102] or lymphocytes [66] triggering the second wave of cell migration, mostly of mononuclear cells. Furthermore, activated neutrophils produce lipid mediators such as resolvins and protectins that inhibit neutrophil recruitment [25,58,66] and "find me" and "eat me" signals that initiate the elimination of aged PMN by macrophages [14].…”