resolvin-d3 and Inflammation

Advances in our understanding of the mechanisms that bring about the resolution of acute inflammation have uncovered a new genus of pro-resolving lipid mediators that include the lipoxin, resolvin, protectin and maresin families, collectively called specialized pro-resolving mediators. Synthetic versions of these mediators have potent bioactions when administered in vivo. In animal experiments, the mediators evoke anti-inflammatory and novel pro-resolving mechanisms, and enhance microbial clearance. Although they have been identified in inflammation resolution, specialized pro-resolving mediators are conserved structures that also function in host defence, pain, organ protection and tissue remodelling. This Review covers the mechanisms of specialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us to understand their physiological functions.

Topics: Animals; Chronic Disease; Docosahexaenoic Acids; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Humans; Immunity; Infections; Inflammation; Inflammation Mediators; Models, Biological; Pain; Regeneration; Translational Research, Biomedical; Wound Healing

Resolvins, a new family from the endogenous specialized pro-resolving mediators (SPMs), promote the resolution of the inflammatory response. Resolvin D3 (RvD3), a docosahexaenoic acid (DHA) product, has been known to suppress the inflammatory response. However, the anti-inflammatory and neuroprotective effects of RvD3 are not known in a model of spinal cord injury (SCI). Here, we investigated the anti-inflammatory and neuroprotective effect of RvD3 in a mouse model of SCI. Processes associated with anti-inflammation and angiogenesis were studied in RAW 264.7 cells and the human brain endothelial cell line hCMEC/D3, respectively. Additionally, female C57BL/6 mice were subjected to moderate compression SCI (20-g weight compression for 1 min) followed by intrathecal injection of vehicle or RvD3 (1 μg/20 μL) at 1 h post-SCI. RvD3 decreased the lipopolysaccharide (LPS)-induced production of inflammatory mediators and nitric oxide (NO) in RAW 264.7 cells and promoted an angiogenic effect in the hCMEC/D3 cell line. Treatment with RvD3 improved locomotor recovery and reduced thermal hyperalgesia in SCI mice compared with vehicle treatment at 14 days post-SCI. Remarkably, RvD3-treated mice exhibited reduced expression of inflammatory cytokines (TNF-α, IL6, IL1β) and chemokines (CCL2, CCL3). Also, RvD3-treated mice exhibited increased expression of tight junction proteins such as zonula occludens (ZO)-1 and occludin. Furthermore, immunohistochemistry showed a decreased level of gliosis (GFAP, Iba-1) and neuroinflammation (CD68, TGF-β) and enhanced neuroprotection. These data provide evidence that intrathecal injection of RvD3 represents a promising therapeutic strategy to promote inflammatory resolution, neuroprotection, and neurological functional recovery following SCI.

Topics: Animals; Anti-Inflammatory Agents; Cell Movement; Cicatrix; Endothelial Cells; Fatty Acids, Unsaturated; Female; Fibrosis; Inflammation; Locomotion; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Neuroglia; Neuroprotection; Neuroprotective Agents; Nitric Oxide; Pain; Phenotype; RAW 264.7 Cells; Recovery of Function; Spinal Cord Injuries; Tight Junction Proteins

Topics: Animals; Antineoplastic Agents; Aspirin; Chemokine CCL2; Chemokines; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Eicosanoids; Fatty Acids, Unsaturated; Female; Inflammation; Lipoxins; Macrophages; Metabolomics; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microtubule-Associated Proteins; Neoplasm Metastasis; Neoplasms; Nerve Tissue Proteins; Phagocytosis; Plasminogen Inactivators; Prostaglandins

Resolution of infection and inflammation is governed by innate immune cells. The resolvin family of n-3 mediators produced by resolving exudates stimulates clearance of neutrophils and attenuates pro-inflammatory signals. Using metabololipidomics, endogenous resolvin D3 (RvD3) was identified in self-resolving exudates during active E. coli infection. Through a new, independent synthetic route for RvD3, we matched endogenous and synthetic RvD3 and determined that RvD3 (ng doses) potently reduced the resolution interval (R

Topics: Animals; Cytokines; Escherichia coli; Escherichia coli Infections; Fatty Acids, Unsaturated; Inflammation; Macrophages; Male; Mice; Neutrophils; Peritonitis

Aging is associated with an overt inflammatory phenotype and physiological decline. Specialized proresolving lipid mediators (SPMs) are endogenous autacoids that actively promote resolution of inflammation. In this study, we investigated resolution of acute inflammation in aging and the roles of SPMs. Using a self-resolving peritonitis and resolution indices coupled with lipid mediator metabololipidomics, we found that aged mice had both delayed resolution and reduced SPMs. The SPM precursor docosahexaenoic acid accelerated resolution via increased SPMs and promoted human monocyte reprogramming. In aged mice, novel nano-proresolving medicines carrying aspirin-triggered resolvins D1 and D3 reduced inflammation by promoting efferocytosis. These findings provide evidence for age-dependent resolution pathways in acute inflammation and novel means to activate resolution.

Topics: Aging; Animals; Aspirin; Autacoids; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Humans; Inflammation; Inflammation Mediators; Leukocytes, Mononuclear; Macrophages; Male; Metabolomics; Mice; Mice, Inbred BALB C; Nanomedicine; Peritonitis; Principal Component Analysis; Zymosan

Resolvins are a family of n-3 lipid mediators initially identified in resolving inflammatory exudates that temper inflammatory responses to promote catabasis. Here, temporal metabololipidomics with self-limited resolving exudates revealed that resolvin (Rv) D3 has a distinct time frame from other lipid mediators, appearing late in the resolution phase. Using synthetic materials prepared by stereocontrolled total organic synthesis and metabololipidomics, we established complete stereochemistry of RvD3 and its aspirin-triggered 17R-epimer (AT-RvD3). Both synthetic resolvins potently regulated neutrophils and mediators, reducing murine peritonitis and dermal inflammation. RvD3 and AT-RvD3 displayed leukocyte-directed actions, e.g., blocking human neutrophil transmigration and enhancing macrophage phagocytosis and efferocytosis. These results position RvD3 uniquely within the inflammation-resolution time frame to vantage and contribute to the beneficial actions of aspirin and essential n-3 fatty acids.

Topics: Animals; Aspirin; Cytokines; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Humans; Immunosuppressive Agents; Inflammation; Macrophages; Metabolome; Mice; Neutrophils; Peritonitis; Phagocytosis; Receptors, G-Protein-Coupled; Stereoisomerism; Tandem Mass Spectrometry