Chapter 20 : Macrophage Proresolving Mediators—the When and Where

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Inflammation is the organism’s response to local injury in vascularized tissues programmed to traffic leukocytes and plasma delivery to an injured site or point of bacterial invasion ( ); this protective response, when uncontrolled in humans, is associated with many widely occurring diseases. These include cardiovascular, metabolic, and the classic inflammatory diseases, e.g., arthritis and periodontal disease, along with cancers (reviewed in reference ). Nonresolving inflammation is now widely acknowledged as a major driver in most of these diseases (for a review, see reference ). The classical view of the resolution phase of the acute inflammatory response as understood and presented in pathology textbooks ( ) as well as in medical dictionaries ( ) was that local inflammatory chemical messengers and cells were diluted at the site (dilution of chemotactic gradient), hence halting further leukocyte recruitment and resolving the exudate or battlefield of inflammation ( ). The historical perspective on the origins and concepts in the medical community regarding the resolution of inflammation apparently trace back as early as 11th-century Europe, and interested readers can refer to a recent review ( ).

Citation: Dalli J, Serhan C. 2017. Macrophage Proresolving Mediators—the When and Where, p 367-383. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0001-2014
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Figure 1

SPM identification in human macrophages: regulation during efferocytosis and by neutrophil microparticles. Macrophages were incubated with PMN microparticles before addition of apoptotic (Apo) PMNs. Representative MRM traces for identified LMs. Accompanying MS/MS spectra used for SPM identification. Specific bioactive LM and precursor/pathway markers where Q1, M-H (parent ion); and Q3, diagnostic ion in the MS/MS (daughter ion), along with mean ± standard error of the mean (SEM) values for each of the mediators are identified. Quantification and values obtained after PMN (3 × 10 PMNs) and microparticle (2 × 10 microparticles) incubations. The detection limit was ∼1 pg. *Below limits. = 4 distinct cell preparations. See reference and the text for further details.

Citation: Dalli J, Serhan C. 2017. Macrophage Proresolving Mediators—the When and Where, p 367-383. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0001-2014
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Figure 2

Upregulation of SPMs in macrophages (Mɸ) by apoptotic PMNs and PMN microparticles (MPs). Incubations were conducted as in Fig. 1 ; LMs were identified and quantified by LC-MS/MS. D-series resolvins, protectins, and maresins. Lipoxins. Prostaglandins and thromboxanes. Results are expressed as mean ± SEM; = 4 distinct cell preparations. * < 0.05 versus macrophage group; ** < 0.01 versus macrophage group; < 0.05 versus macrophage plus Apo PMN group. Uptake of the carboxyfluorescein diacetate succinimidyl ester (CFDA)-labeled Apo PMNs was monitored after incubation with the indicated MP concentrations. Results are expressed as mean ± SEM ( = 4 distinct cell preparations). * < 0.05 versus macrophage plus PMN group; ** < 0.01 versus macrophage plus Apo PMN group. Schematic highlighting the contribution of apoptotic PMNs and MPs to SPM biosynthesis in macrophages. See reference and the text for further details.

Citation: Dalli J, Serhan C. 2017. Macrophage Proresolving Mediators—the When and Where, p 367-383. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0001-2014
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Figure 3

Distinct macrophage subtypes display characteristic LM profiles. Human M1 and M2 macrophages were obtained by incubating peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor, gamma interferon, and lipopolysaccharide or macrophage colony-stimulating factor and IL-4, respectively, and LM profiles assessed by LC-MS/MS. Results are representative on = 6 to 8 separate cell preparations. The original results were obtained in reference and are replotted here.

Citation: Dalli J, Serhan C. 2017. Macrophage Proresolving Mediators—the When and Where, p 367-383. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0001-2014
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Figure 4

The macrophage-derived proresolving mediator MaR1 stimulates tissue regeneration. Anterior portions of brown planaria were surgically removed, planaria were exposed to vehicle or MaR1, and regeneration was assessed 4 days after surgery using fluorescently conjugated lectin to visualize secretory cells. After surgery, planaria were kept in water-containing vehicle (Veh) or the indicated concentrations of MaR1. We direct interested readers to reference for detailed experimental conditions. Results are mean ± SEM ( = 5 planaria/group). * < 0.05; ** < 0.01; *** < 0.001 versus vehicle alone.

Citation: Dalli J, Serhan C. 2017. Macrophage Proresolving Mediators—the When and Where, p 367-383. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0001-2014
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Figure 5

Maresins and RvD1 promote macrophage phenotype switch. M1 macrophages were incubated with vehicle, 13,14-epoxy-maresin, MaR1, or RvD1 for 6 h. Expression of M1 (CD54, CD80) and M2 (CD163, CD206) was assessed by flow cytometry using fluorescently conjugated antibodies. Results are representative of = 3 for each incubation condition. MFI, mean fluorescence intensity. See the text for additional details and reference for the original data set.

Citation: Dalli J, Serhan C. 2017. Macrophage Proresolving Mediators—the When and Where, p 367-383. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0001-2014
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Figure 6

Maresin biosynthesis and actions. DHA is converted by human 12-LOX through a lipoxygenase reaction involving the abstraction of hydrogen and the antarafacial addition of molecular oxygen at carbon 14 to produce 14-HpDHA, which is also converted to the 13,14-epoxide by the same enzyme ( ), denoted 13,14-epoxide-maresin, which is further converted to the bioactive MaR1, which promotes resolution, reduces pain signaling, and promotes tissue regeneration. See the text for further details, as well as references , and . The epoxide 13,14-epoxy-maresin is also bioactive and inhibits LTA hydrolase, limiting the production of LTB as well as the conversion of AA to 12-HpETE. These actions of the maresin epoxide indicate that activation of the pathway leads to downregulation of proinflammatory mediators during resolution.

Citation: Dalli J, Serhan C. 2017. Macrophage Proresolving Mediators—the When and Where, p 367-383. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0001-2014
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