Matthew Spite

Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions

The endogenous cellular and molecular mechanisms that control acute inflammation and its resolution are of wide interest. Using self-resolving inflammatory exudates and lipidomics, we have identified a new pathway involving biosynthesis of potent antiinflammatory and proresolving mediators from the essential fatty acid docosahexaenoic acid (DHA) by macrophages (MΦs). During the resolution of mouse peritonitis, exudates accumulated both 17-hydroxydocosahexaenoic acid, a known marker of 17S-D series resolvin (Rv) and protectin biosynthesis, and 14S-hydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid from endogenous DHA. Addition of either DHA or 14S-hydroperoxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid to activated MΦs converted these substrates to novel dihydroxy-containing products that possessed potent antiinflammatory and proresolving activity with a potency similar to resolvin E1, 5S,12R,18R-trihydroxyeicosa-6Z,8E,10E,14Z,16E-pentaenoic acid, and protectin D1, 10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Stable isotope incorporation, intermediate trapping, and characterization of physical and biological properties of the products demonstrated a novel 14-lipoxygenase pathway, generating bioactive 7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, coined MΦ mediator in resolving inflammation (maresin), which enhances resolution. These findings suggest that maresins and this new metabolome may be involved in some of the beneficial actions of DHA and MΦs in tissue homeostasis, inflammation resolution, wound healing, and host defense.

Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis

A growing body of evidence indicates that resolution of acute inflammation is an active process. Resolvins are a new family of lipid mediators enzymatically generated within resolution networks that possess unique and specific functions to orchestrate catabasis, the phase in which disease declines. Resolvin D2 (RvD2) was originally identified in resolving exudates, yet its individual contribution in resolution remained to be elucidated. Here, we establish RvD2’s potent stereoselective actions in reducing excessive neutrophil trafficking to inflammatory loci. RvD2 decreased leukocyte–endothelial interactions in vivo by endothelial-dependent nitric oxide production, and by direct modulation of leukocyte adhesion receptor expression. In mice with microbial sepsis initiated by caecal ligation and puncture, RvD2 sharply decreased both local and systemic bacterial burden, excessive cytokine production and neutrophil recruitment, while increasing peritoneal mononuclear cells and macrophage phagocytosis. These multi-level pro-resolving actions of RvD2 translate to increased survival from sepsis induced by caecal ligation and puncture and surgery. Together, these results identify RvD2 as a potent endogenous regulator of excessive inflammatory responses that acts via multiple cellular targets to stimulate resolution and preserve immune vigilance.

Novel Lipid Mediators Promote Resolution of Acute Inflammation Impact of Aspirin and Statins

The resolution of acute inflammation is a process that allows for inflamed tissues to return to homeostasis. Resolution was held to be a passive process, a concept now overturned with new evidence demonstrating that resolution is actively orchestrated by distinct cellular events and endogenous chemical mediators. Among these, lipid mediators, such as the lipoxins, resolvins, protectins, and newly identified maresins, have emerged as a novel genus of potent and stereoselective players that counter-regulate excessive acute inflammation and stimulate molecular and cellular events that define resolution. Given that uncontrolled, chronic inflammation is associated with many cardiovascular pathologies, an appreciation of the endogenous pathways and mediators that control timely resolution can open new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation, as well as correcting the impact of chronic inflammation in cardiovascular disorders. Here, we overview and update the biosynthesis and actions of proresolving lipid mediators, highlighting their diverse protective roles relevant to vascular systems and their relation to aspirin and statin therapies.

Measurement of stellar age from uranium decay

The ages of the oldest stars in the Galaxy indicate when star formation began, and provide a minimum age for the Universe. Radioactive dating of meteoritic material and stars relies on comparing the present abundance ratios of radioactive and stable nuclear species to the theoretically predicted ratios of their production. The radioisotope 232Th (half-life 14 Gyr) has been used to date Galactic stars, but it decays by only a factor of two over the lifetime of the Universe. 238U (half-life 4.5 Gyr) is in principle a more precise age indicator, but even its strongest spectral line, from singly ionized uranium at a wavelength of 385.957 nm, has previously not been detected in stars. Here we report a measurement of this line in the very metal-poor star CS31082-0018, a star which is strongly overabundant in its heavy elements. The derived uranium abundance, log(U/H) = -13.7 ± 0.14 ± 0.12 yields an age of 12.5 ± 3 Gyr, though this is still model dependent. The observation of this cosmochronometer gives the most direct age determination of the Galaxy. Also, with improved theoretical and laboratory data, it will provide a highly precise lower limit to the age of the Universe.

Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese-diabetic mice

Type 2 diabetes and obesity have emerged as global public health crises. Adipose tissue expansion in obesity promotes accumulation of classically activated macrophages that perpetuate chronic inflammation and sustain insulin resistance. Acute inflammation normally resolves in an actively orchestrated series of molecular and cellular events that ensures return to homeostasis after an inflammatory insult, a process regulated in part by endogenous lipid mediators such as the resolvins. In this study, we sought to determine whether stimulating resolution with resolvin D1 (RvD1) improves insulin sensitivity by resolving chronic inflammation associated with obesity. In male leptin receptor‐deficient (db/db) mice, treatment with RvD1 (2 μg/kg) improved glucose tolerance, decreased fasting blood glucose, and increased insulin‐stimulated Akt phosphorylation in adipose tissue relative to vehicle‐treated mice. Treatment with RvD1 increased adiponectin production, while expression of IL‐6 in adipose tissue was decreased. The formation of crown‐like structures rich in inflammatory F4/80+ CD11c+ macrophages was reduced by >50% in adipose tissue by RvD1 and was associated with an increased percentage of F4/80+ cells expressing macrophage galactose‐type C‐type lectin 1 (MGL‐1), a marker of alternatively activated macrophages. These results suggest that stimulating resolution with the endogenous proresolving mediator RvD1 could provide a novel therapeutic strategy for treating obesity‐induced diabetes.—Hellmann, J., Tang, Y., Kosuri, M., Bhatnagar, A., Spite, M. Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese‐diabetic mice. FASEB J. 25, 2399–2407 (2011). www.fasebj.org

Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases.

Inflammation is associated with the development of diseases characterized by altered nutrient metabolism. Although an acute inflammatory response is host-protective and normally self-limited, chronic low-grade inflammation associated with metabolic diseases is sustained and detrimental. The resolution of inflammation involves the termination of neutrophil recruitment, counterregulation of proinflammatory mediators, stimulation of macrophage-mediated clearance, and tissue remodeling. Specialized proresolving lipid mediators (SPMs)-resolvins, protectins, and maresins-are novel autacoids that resolve inflammation, protect organs, and stimulate tissue regeneration. Here, we review evidence that the failure of resolution programs contributes to metabolic diseases and that SPMs may play pivotal roles in their resolution.

Cutting Edge: Humanized Nano-Proresolving Medicines Mimic Inflammation-Resolution and Enhance Wound Healing

Endogenous microparticles (MPs) were systematically profiled during the time course of self-limited inflammation. Precursors for specialized proresolving lipid mediators were identified in MPs from inflammatory exudates using liquid chromatography tandem mass spectrometry-based metabolomics. Hence, we postulated that formation of anti-inflammatory and proresolving lipid mediators could underlie beneficial effects attributed to MPs and that this process could serve as a basis for biomimicry. Using human neutrophil-derived MPs, we constructed novel nanoparticles (NPs) containing aspirin-triggered resolvin D1 or a lipoxin A4 analog. Enriched NPs dramatically reduced polymorphonuclear cell influx in murine peritonitis, shortened resolution intervals, and exhibited proresolving actions accelerating keratinocyte healing. The enriched NPs protected against inflammation in the temporomandibular joint. These findings indicate that humanized NPs, termed nano-proresolving medicines, are mimetics of endogenous resolving mechanisms, possess potent beneficial bioactions, can reduce nanotoxicity, and offer new therapeutic approaches.

Deficiency of the Leukotriene B4 Receptor, BLT-1, Protects against Systemic Insulin Resistance in Diet-Induced Obesity

Chronic inflammation is an underlying factor linking obesity with insulin resistance. Diet-induced obesity promotes an increase in circulating levels of inflammatory monocytes and their infiltration into expanding adipose tissue. Nevertheless, the endogenous pathways that trigger and sustain chronic low-grade inflammation in obesity are incompletely understood. In this study, we report that a high-fat diet selectively increases the circulating levels of CD11b+ monocytes in wild-type mice that express leukotriene B4 receptor, BLT-1, and that this increase is abolished in BLT-1–null mice. The accumulation of classically activated (M1) adipose tissue macrophages (ATMs) and the expression of proinflammatory cytokines and chemokines (i.e., IL-6 and Ccl2) was largely blunted in adipose tissue of obese BLT-1−/− mice, whereas the ratio of alternatively activated (M2) ATMs to M1 ATMs was increased. Obese BLT-1−/− mice were protected from systemic glucose and insulin intolerance and this was associated with a decrease in inflammation in adipose tissue and liver and a decrease in hepatic triglyceride accumulation. Deletion of BLT-1 prevented high fat-induced loss of insulin signaling in liver and skeletal muscle. These observations elucidate a novel role of chemoattractant receptor, BLT-1, in promoting monocyte trafficking to adipose tissue and promoting chronic inflammation in obesity and could lead to the identification of new therapeutic targets for treating insulin resistance in obesity.

Resolvins: Anti-Inflammatory and Proresolving Mediators Derived from Omega-3 Polyunsaturated Fatty Acids

Omega-3 polyunsaturated fatty acids (PUFAs) are essential to health, and deficiencies in these PUFAs are linked to chronic disease. Although important insights into the diverse biological roles of PUFAs have been made, the mechanistic basis underlying their protective actions is still emerging. Studies over the past decade have elucidated that omega-3 PUFAs are enzymatically converted into bioactive autacoids that have inflammation-resolving properties. Among these, resolvins have emerged as an important family that has potent and stereospecific immunomodulatory roles, elucidation of which has contributed to a growing body of literature demonstrating that resolution of acute inflammation is an active process. In addition to their direct interactions with immune cells, resolvins have effects on nonimmune cells as well, suggesting a much broader role in biological systems than originally appreciated. In this review, we describe the endogenous biosynthesis and immunomodulatory actions of resolvins and highlight their emerging roles in health and disease.

Proresolution Therapy for the Treatment of Delayed Healing of Diabetic Wounds

Obesity and type 2 diabetes are emerging global epidemics associated with chronic, low-grade inflammation. A characteristic feature of type 2 diabetes is delayed wound healing, which increases the risk of recurrent infections, tissue necrosis, and limb amputation. In health, inflammation is actively resolved by endogenous mediators, such as the resolvins. D-series resolvins are generated from docosahexaenoic acid (DHA) and promote macrophage-mediated clearance of microbes and apoptotic cells. However, it is not clear how type 2 diabetes affects the resolution of inflammation. Here, we report that resolution of acute peritonitis is delayed in obese diabetic (db/db) mice. Altered resolution was associated with decreased apoptotic cell and Fc receptor–mediated macrophage clearance. Treatment with resolvin D1 (RvD1) enhanced resolution of peritonitis, decreased accumulation of apoptotic thymocytes in diabetic mice, and stimulated diabetic macrophage phagocytosis. Conversion of DHA to monohydroxydocosanoids, markers of resolvin biosynthesis, was attenuated in diabetic wounds, and local application of RvD1 accelerated wound closure and decreased accumulation of apoptotic cells and macrophages in the wounds. These findings support the notion that diabetes impairs resolution of wound healing and demonstrate that stimulating resolution with proresolving lipid mediators could be a novel approach to treating chronic, nonhealing wounds in patients with diabetes.