An LGR6 frameshift variant abrogates receptor expression on select leukocyte subsets and is associated with viral infections.

The leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) was recently identified as the cognate receptor for the proresolving mediator maresin 1 (MaR1). To address the biological role of LGR6 in humans, we investigated the functional impact of a genetic variant in the gene encoding for LGR6, which is predicted to lead to a frameshift mutation in one of the receptor isoforms, on both receptor expression and immune cell responses. In neutrophils, monocytes, and natural killer (NK) cells from volunteers homozygous for this variant, we found a significant downregulation in the expression of LGR6 when compared with controls without the variant; whereas the LGR6 expression was essentially similar in monocyte-derived macrophages and CD8+ T cells.

Resolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease.

While cardiovascular disease (CVD) is one of the major co-morbidities in patients with rheumatoid arthritis (RA), the mechanism(s) that contribute to CVD in patients with RA remain to be fully elucidated. Herein, we observe that plasma concentrations of 13-series resolvin (RvT)4 negatively correlate with vascular lipid load in mouse inflammatory arthritis. Administration of RvT4 to male arthritic mice fed an atherogenic diet significantly reduces atherosclerosis.

Efferocyte-Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1-Mediated Activation of Glycolysis.

Clearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental process. Herein, the authors reported that breakdown of ACs leads to upregulation of 12-lipoxygenase in macrophages.

Aspirin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal cancer.

Inflammation is linked with carcinogenesis in many types of cancer including colorectal cancer (CRC). Aspirin is recommended for the prevention of CRC, although the mechanism(s) mediating its immunomodulatory actions remain incompletely understood. Here, we demonstrate that aspirin increased concentrations of the immune-regulatory aspirin-triggered specialized proresolving mediators (AT-SPMs), including AT-lipoxin A and AT-resolvin D1, in colonic tissues during inflammation-associated CRC (I-CRC).

Stereoselective Synthesis, Configurational Assignment and Biological Evaluations of the Lipid Mediator RvD2.

Herein we report the first total synthesis of RvD2 , an endogenously formed mediator biosynthesized from the omega-3 fatty acid n-3 docosapentaenoic acid. The key steps are the Midland Alpine borane reduction, Sonogashira cross-coupling reactions, and a Z-selective alkyne reduction protocol, yielding RvD2 methyl ester in 13 % yield over 12 steps (longest linear sequence). The physical property data (UV chromophore, chromatography and MS/MS fragmentation) of the synthetic lipid mediator matched those obtained from biologically produced material.

Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses: A Randomized Double-Blind Placebo-Controlled Study.

Rationale: Specialized pro-resolving mediators (SPM-lipoxins, resolvins, protectins, and maresins) are produced via the enzymatic conversion of essential fatty acids, including the omega-3 fatty acids docosahexaenoic acid and n-3 docosapentaenoic acid. These mediators exert potent leukocyte directed actions and control vascular inflammation. Supplementation of animals and humans with essential fatty acids, in particular omega-3 fatty acids, exerts protective actions reducing vascular and systemic inflammation.

Resolving Inflammation: Synthesis, Configurational Assignment, and Biological Evaluations of RvD1.

New drugs that can resolve inflammation without immunosuppressive effects are at the medicinal chemistry frontier. Pro-resolving endogenously formed small molecules, that is, the resolvins, are excellent candidates displaying such bioactions. The first total synthesis of the specialized pro-resolving mediator RvD1 has been achieved using the underutilized sp -sp Negishi cross coupling reaction and an alkyne hydrosilylation-protodesilylation protocol.

PD Pathway Regulates Human Monocyte Differentiation and Macrophage Function.

Macrophages are central in orchestrating the clearance of apoptotic cells and cellular debris during inflammation, with the mechanism(s) regulating this process remaining of interest. Herein, we found that the n-3 docosapentaenoic acid-derived protectin (PD) biosynthetic pathway regulated the differentiation of human monocytes, altering macrophage phenotype, efferocytosis, and bacterial phagocytosis. Using lipid mediator profiling, human primary cells and recombinant enzymes we found that human 15-lipoxygenases initiate the PD pathway catalyzing the formation of an allylic epoxide.

Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis.

Background: The aim was to investigate CD4T-cell subsets, immune cells and their cytokine profiles in blood and synovial compartments in rheumatoid arthritis (RA) and inflammatory osteoarthritis (OA) to define specific immune signatures.

Methods: Peripheral blood, synovial fluid (SF) and synovial membranes (SM) of RA and OA patients were analyzed. CD4T-cell subset frequencies were determined by flow cytometry, and cytokine concentrations in serum and SF were measured by ELISA.