Adipose tissue IL-18 production is independent of caspase-1 and caspase-11.

BACKGROUND: Inflammation in adipose tissue, resulting from imbalanced caloric intake and energy expenditure, contributes to the metabolic dysregulation observed in obesity. The production of inflammatory cytokines, such as IL-1ß and IL-18, plays a key role in this process. While IL-1ß promotes insulin resistance and diabetes, IL-18 regulates energy expenditure and food intake. Previous studies have suggested that caspase-1, activated by the Nlrp3 inflammasome in response to lipid excess, mediates IL-1ß production, whereas activated by the Nlrp1b inflammasome in response to energy excess, mediates IL-18 production. However, this has not been formally tested. METHODS: Wild-type and caspase-1-deficient Balb/c mice, carrying the Nlrp1b1 allele, were fed with regular chow or a high-fat diet for twelve weeks. Food intake and mass gain were recorded weekly. At the end of the twelve weeks, glucose tolerance and insulin resistance were evaluated. Mature IL-18 protein levels and the inflammatory process in the adipose tissue were determined. Fasting lipid and cytokine levels were quantified in the sera of the different experimental groups. RESULTS: We found that IL-18 production in adipose tissue is independent of caspase-1 activity, regardless of the metabolic state, while Nlrp3-mediated IL-1ß production remains caspase-1 dependent. Additionally, caspase-1 null Balb/c mice did not develop metabolic abnormalities in response to energy excess from the high-fat diet. CONCLUSION: Our findings suggest that IL-18 production in the adipose tissue is independent of Nlrp3 inflammasome and caspase-1 activation, regardless of caloric food intake. In contrast, Nlrp3-mediated IL-1ß production is caspase-1 dependent. These results provide new insights into the mechanisms underlying cytokine production in the adipose tissue during both homeostatic conditions and metabolic stress, highlighting the distinct roles of caspase-1 and the Nlrp inflammasomes in regulating inflammatory responses.

Ontogenetic changes in the venom of Metlapilcoatlus nummifer, the mexican jumping viper.

The viperid genus Metlapilcoatlus (previously Atropoides) is represented in Mexico by four species: M. olmec, M. mexicanus, M. occidus, and M. nummifer. To date, no studies on their venoms have been reported. Here, we comparatively characterized the venom from M. nummifer neonates (≤8 months of age), young adults (18 months) and adults (≥24 months). We performed biological and enzymatic activities, as well as electrophoretic and RP-HPLC profiling combined with proteomic assignment of major fractions. Venoms from neonates and adults differed in their electrophoretic and chromatographic profiles, indicating that an ontogenetic compositional shift occurs in this species. Protein family assignments showed that neonates produce a venom rich in Snake Venom Metalloproteinases (SVMPs) and Snake Venom Serine Proteases (SVSPs), but lacking Phospholipases A2 (PLA2s). In contrast, adults express abundant venom PLA2s, and lower molecular weight proteins, as evidenced by SDS-PAGE. Functionally, neonate venom did not display PLA2 or procoagulant activities, whereas adult venom did. Hemorrhagic activity was present in both neonate and adult venoms, with similar potencies. Finally, it is of considerable concern that the lethal activity of neither neonate nor adult venoms was neutralized by two therapeutic antivenoms produced in Mexico.

Nlrp1b1 negatively modulates obesity-induced inflammation by promoting IL-18 production.

Obesity-induced inflammation, triggered by lipid-mediated activation of the Nlrp3 inflammasome, results in glucose metabolism alterations and type 2 diabetes. This knowledge has been generated using animals deficient for any of the different components of this inflammasome (Caspase-1, Asc or Nlrp3) in the C57BL/6 background. Unlike C57BL/6 mice, which carry allele 2 of the Nlrp1b gene (Nlrp1b2), Balb/c mice that carry allele 1 (Nlrp1b1) are less prone to develop alterations in the glucose metabolism when fed with a high fat diet. However, the molecular bases for these metabolic differences are unknown. Here we show that the Nlrp1b1 allele down regulates the adipose tissue inflammatory response attenuating glucose intolerance and insulin resistance in obese C57BL/mice. Our results indicate that the positive effects of the Nlrp1b1 inflammasome on glucose tolerance and insulin sensitivity involve IL-18-mediated effects on lipolysis, pointing out that differential expression of allelic variants of genes coding for inflammasome components might control susceptibility or resistance to develop diabetes in obese individuals.

Biochemical and immunochemical characterization of venoms from snakes of the genus Agkistrodon.

In the present work, venoms from five species of the genus Agkistrodon were evaluated in terms of their enzymatic (Phospholipase A2 and caseinolytic) and biological (edema forming, hemorrhagic, procoagulant and lethal) effects. Horses were used to produce monovalent hyperimmune sera against each of three venoms (A. bilineatus, A. contortrix and A. piscivorus) and their neutralizing potency, expressed as Median Effective Dose (ED50), was determined against the venoms of all five species. In terms of PLA2 and caseinolytic activities, all venoms are extremely homogeneous. PLA2 activity is high, while caseinolytic activity is low when in contrast with that of the rattlesnake Crotalus simus. On the other hand, biological activities showed marked interspecific differences, particularly between the species from Mexico and those from the United States. Mexican species displayed higher edema-forming, hemorrhagic and lethal effects than US species, while none of the species studied presented procoagulant activity. All three monovalent hyperimmune sera showed good neutralizing potency against the analyzed venoms. Nonetheless, we observed relevant immunochemical differences among the venoms using ELISA and Western Blot assays. We conclude that the venoms of A. piscivorus (USA) and A. bilineatus would be ideal to use as immunogens for the production of a polyvalent antivenom with good neutralizing potency against the venoms of all the species of the genus.