Novel Proresolving Aspirin-Triggered DHA Pathway

Serhan, Charles N.; Fredman, Gabrielle; Rong, Yang; Karamnov, Sergey; Belayev, Ludmila; Bazán, Nicolás G.; Zhu, Min; Winkler, Jeremy W.; Petasis, Nicos A.

doi:10.1016/j.chembiol.2011.06.008

Cited by 147 publications

(145 citation statements)

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Section: Pathologymentioning

confidence: 99%

“…During the early stages of the repair response after wounding the skin, infiltrating macrophages have an M2 phenotype and their depletion inhibits the formation of a highly vascularized, cellular granulation tissue and of scar tissues (36). Under these conditions, the removal of apoptotic cells (efferocytosis) (37,38) and the presence of TGF-β (39) may skew macrophage function, though demonstration of actual in vivo relevance of these findings is lacking.In a peritoneal model of inflammation, resolution phase macrophages expressed a unique mixed M1-M2 phenotype, and cAMP was essential to restrain M1 activation (40). In humans, chronic venous ulcers (CVU) represent a failure to resolve a chronic inflammatory condition (41).…”

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confidence: 99%

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Macrophage plasticity and polarization: in vivo veritas

2012

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(Retnla, Fizz1), and chitinase 3-like 3 (Chi3l3, Ym1) (14). IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype (4,15,16). STAT-mediated activation of macrophages is regulated by members of the SOCS family. IL-4 and IFN-γ, the latter in concert with TLR stimulation, upregulate SOCS1 and SOCS3, which in turn inhibit the action of STAT1 and STAT3, respectively (17,18).Downstream of, or in parallel with, the IRF/STAT/SOCS pathway, a panel of transcription factors orchestrates polarized macrophage activation. The nuclear receptors PPARγ (19) and PPARδ (20,21) control distinct subsets of genes associated with M2 macrophage activation and oxidative metabolism (Figure 1). Interestingly, STAT6 coordinates and synergizes with both PPARγ (22) and Krüppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function (23, 24). KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPARγ) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-κB activation. KLF2 regulates macrophage activation by inhibiting NF-κB/ HIF-1α activities (25). IL-4 also induces c-Myc activity in human macrophages (26), which controls genes of M2 activation (Scarb1, Alox15, and Mrc1) as well as STAT6 and PPARγ activation (26).TLR engagement leads to NF-κB activation and production of inflammatory mediators (27) associated with M1 macrophages. However, NF-κB activation also activates a genetic program essential for resolution of inflammation (28) and for M2 polarization of tumor-associated macrophages (TAMs) (29). Moreover, induction of p50 NF-κB homodimers is essential for M2 polarization in vitro and in vivo (30). The hypoxia-inducible factors HIF-1α and HIF-2α are expressed differentially in M1- and M2-polarized macrophages (31) and regulate inducible NOS2 (M1) and arginase 1 (M2), respectively. Figure 1Mechanisms of macrophage polarization. The major pathways of macrophage polarization are outlined. The crosstalk between the M1-M2 macrophage-polarizing pathways is also indicated. The balance between activation of STAT1 and STAT3/STAT6 finely regulates macrophage polarization and activity. A predominance of NF-κB and STAT1 activation promotes M1 macrophage polarization, resulting in cytotoxic and inflammatory functions. In contrast, a predominance of STAT3 and STAT6 activation results in M2 macrophage polarization, associated with immune suppression and tumor progression. PPARγ and PPARδ control distinct aspects of M2 macrophage activation and oxidative metabolism. KLF4 and KLF2 participate in the promotion of M2 macrophage functions by cooperating with STAT6 and suppressing the NF-κB/HIF-1α-dependent transcription, respectively. IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing Jmjd3-IRF4 axis to inhibit IRF5-mediated M1 polarization. IL-10 promotes M2 polarization through the induction of p50 NF-κB homodimer, c-Maf, and STAT3 activities. Epigenetic ...

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Section: Pathologymentioning

confidence: 99%

mentioning

confidence: 99%

Macrophage plasticity and polarization: in vivo veritas

2012

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“…The fact that EPA and DHA are the sources of resolvins and protectins implies that there may be human physiological factors, including cyclooxygenase enzyme activity variation, that optimally determine the amounts of these metabolites that are generated and exist in tissue. Thus, it may be that the ingestion of EPA/DHA is more conducive to homeostasis than ingestion or another source of exposure of metabolites, particularly in the setting of optimal diet, exercise, other lifestyle characteristics, and the ingestion of drugs (including aspirin) that can increase the production of resolvins and protectins [28]. Alternatively, the doses and purities of metabolites that are becoming available for research may be significantly more effective for a series of health issues than can be achieved with EPA/DHA ingestion.…”

Section: Challenges In Translating Knowledge To Improve Human Cardiovmentioning

confidence: 99%

Fish Oil Metabolites: Translating Promising Findings from Bench to bedside to Reduce Cardiovascular Disease

Champagne²,

Garigen³

et al. 2012

J Glycom Lipidom

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Cardiovascular disease is an inflammatory process and the leading cause of death in the United States. Novel omega-3 derived potent lipid mediators, termed resolvins and protectins, have been identified as major pathophysiologic players in the resolution phase of the inflammatory response. Potent lipid mediators offer tremendous metabolic and pathophysiologic insights in regard to the risk and treatment of cardiovascular disease. In this review, resolvins and protectins are described and analyzed as accelerators of discovery via their potential role as biomarkers for research and clinical decision making in cardiovascular disease. Specific barriers relating to biomarker validation, laboratory methods, and improvement of risk models are introduced and discussed.

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“…In addition, other anti-inflammatory and proresolving derivates so-called resolvins, protectins and maresins are produced from EPA and DHA from the COX M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 13 and LOX pathways. Resolvin E1 (RvE1), RvE2 and RvE3 are produced from EPA and RvD1, RvD2 and RvD5 are biosynthesized from DHA (reviewed in (Serhan, 2007;Serhan et al, 2011). When produced in the brain, protectins are referred to as neuroprotectins (Bazan, 2012).…”

Section: N-3 Pufa Are Potent Regulators Of Neuroinflammatory Processesmentioning

confidence: 99%