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The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate` (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP (1). BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet (2). Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown (2-6). We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing [K.sup.+] efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome--mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome., The NLRP3 inflammasome controls the activation of caspase-1 and the release of the pro-inflammatory cytokines IL-1β and IL-18 in macrophages (7-11). It is an important innate immune sensor that is [...]

We previously demonstrated that low biosynthesis of ω-3 fatty acid-derived proresolution mediators, termed protectins, is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high-fat diet-fed mice (1). These findings prompted a more direct study of the therapeutic potential of protectins for the treatment of metabolic disorders. Herein we show that protectin DX (PDX) exerts an unanticipated glucoregulatory activity that is distinct from its anti-inflammatory actions. We found that PDX selectively stimulated the release of the prototypic myokine interleukin-6 (IL-6) from skeletal muscle and thereby initiated a myokine-liver signaling axis, which blunted hepatic glucose production via signal transducer and activator of transcription 3 (STAT3)-mediated transcriptional suppression of the gluconeogenic program. These effects of PDX were abrogated in //6-null mice. PDX also activated AMP-activated protein kinase (AMPK); however, it did so in an IL-6-independent manner. Notably, we demonstrated that administration of PDX to obese diabetic db/db mice raises skeletal muscle IL-6 levels and substantially improves their insulin sensitivity without any impact on adipose tissue inflammation. Our findings thus support the development of PDX-based selective muscle IL-6 secretagogues as a new class of therapy for the treatment of insulin resistance and type 2 diabetes., PDX ((10S,17S)-dihydroxydocosa-(4Z,7Z,11E,13Z,15E,19Z)-hexaenoic acid), is produced via sequential lipoxygenation of docosahexaenoic acid (DHA; 22:6 n-3) (2,3) and can be found together with the first identified protectin, protectin D1(PD1;(10R,17S)-dihydroxydocosa-(4Z,7Z,11E,13E,15Z,19Z)-hexaenoic acid), in mouse [...]

Although several homing receptors are known to be differentially expressed by Tregs in lymphoid tissues compared with those found in peripheral tissues, it remains unclear whether these cells traffic between the two locations. In this issue of the JCI, Tomura et al. report steadystate Treg migration from the skin to draining LNs in mice. Furthermore, they report that not only does skin inflammation exacerbate LN-directed Treg homing, it also triggers reverse circulation of Tregs from LNs to skin, whereby these cells contribute to regulation of the immune response. These results now form a new framework for our understanding of Treg homing., Memory T cells are disseminated to lymphoid and nonlymphoid tissues throughout the body, and their migration to respective tissues is tightly regulated by adhesion molecules and chemokine receptors (Table 1). [...]

ABSTRACT Antiangiogenic compounds are gaining more and more interest as a new approach in the prevention and treatment of cancer and inflammatory diseases. The objective of this study was the [...]